Methods and compositions for treating diseases related to imbalance of essential fatty acids

ABSTRACT

This invention relates to compositions containing combinations of a balanced phosphatidylcholine composition and one or more cannabinoids, a natural or synthetic derivative thereof, or a salt thereof, and kits containing such combinations and methods of using such combinations to treat subjects suffering from an imbalance of fatty acids and related diseases or disorders. This invention also relates to the synergistic effect of such combination therapies in humans.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/969,070, filed Mar. 21, 2014, U.S. Provisional Application No.61/969,068, filed Mar. 21, 2014, U.S. Provisional Application No.61/969,063, filed Mar. 21, 2014, and U.S. Provisional Application No.61/969,069, filed Mar. 21, 2014, the entire contents of each of whichare incorporated herein by reference.

FIELD OF THE INVENTION

Described herein is a cannabinoid-based combination therapy suitable forlocal and systemic delivery to a subject; compositions for deliveringsuch pharmaceutically active agents and the use of such compositions intreating and preventing diseases and disorders related to imbalance ofessential fatty acids.

I. BACKGROUND OF THE INVENTION

There are a wide variety of diseases and disorders that are caused by orresult from cell membrane dysfunction and imbalance and derangement offatty acids. It has been discovered that diseases and disorders such aseizures, Alzheimer's disease, depression, and atherosclerosis areeither caused by or result in or from an imbalance of essential fattyacids in cell membranes.

Seizures

Over 53 million people worldwide suffer from epilepsy. Epilepsyprimarily affects children and young adults. Epilepsy and seizuresaffect nearly 3 million Americans of all ages, at an estimated annualcost of $17.6 billion in direct and indirect costs. Approximately200,000 new cases of seizures and epilepsy occur each year. Ten percentof the American population will experience a seizure in their lifetime.Almost 50% of new epilepsy cases occur prior to age 25. About 28% ofepileptic patients have intractable epilepsy that is resistant toantiepileptic treatment [Antiepileptic Drugs; eds. R. H. Levy, R. H.Mattson and B. S. Meldrum; 4th Edition, Raven Press, NY, N.Y.; Aicardi,Epilepsy in children, 2d Edition, Raven Press, 1994].

A seizure is a paroxysmal event due to abnormal, excessive,hypersynchronous discharges from an aggregate of central nervous system(CNS) neurons, while epilepsy is a condition in which a person hasrecurrent seizures due to a chronic, underlying process. Experimentaland clinical data indicate that the occurrence of repeated seizures canlead to an epileptic condition. Abnormal electrical discharges can arisein the brain due to various electrical or chemical stimuli. Certainregions of the brain including the temporal lobe and the deep nuclearaggregates of the motor cortex, the amygdala and the hippocampalstructures of the limbic system are particularly sensitive to abnormalelectrical discharges. An alteration in membrane permeability toextracellular calcium appears to be a critical event in the genesis ofthese abnormal electrical discharges and probably precedes paroxysmalneuronal discharge associated with epileptic seizures.

Epilepsy is a collective designation for a group of central nervoussystem disorders having in common the spontaneous occurrence of seizuresassociated with the disturbance or loss of consciousness. These seizuresare usually, but not always, associated with characteristic bodymovements (convulsions) and sometimes autonomic hyperactivity. Seizurein epilepsy detonation is believed to originate in the non-specificsubcortical mesodiencephalic reticular systems and diffuse bilaterallyinto the cerebral cortex. The motor cortex, the amygdala and thehippocampus have a low threshold and high susceptibility to seizurepossibly due to the vulnerability of their vasculature to compressionand biochemical disturbances. See, e.g., Glaser, “The Epilepsies,”Textbook of Medicine, Beeson and McDermott, eds., W B Saunders Co.,Philadelphia, 1975, pp. 723-24.

Epileptic seizures are divided into partial and generalized seizures onthe basis of the clinical manifestations of the attacks and theelectroencephalographic (EEG) pattern. Each of these two generalepileptic categories is then further subdivided into three or moresubcategories depending on the classification scheme employed. TheInternational Classification of Epileptic Seizures divides seizures intoi) partial seizures (beginning locally) including simple partialseizures (consciousness not impaired) with motor symptoms, withsomatosensory or special sensory symptoms, and with autonomic symptoms,ii) complex partial seizures (with impairment of consciousness)including beginning as simple partial seizures and progressing toimpairment of consciousness, with no other features, with features as insimple partial seizures, with automatisms, with impairment ofconsciousness at onset, with no other features, with features as insimple partial seizures, and with automatisms, iii) partial seizuressecondarily generalized, iv) generalized seizures (bilaterallysymmetrical, without local onset) including absence seizures, atypicalabsence seizures, myoclonic seizures, clonic seizures, tonic seizures,tonic-clonic seizures, and atonic seizures) and v) unclassifiedepileptic seizures (data inadequate or incomplete).

Accurate diagnosis of epilepsy and seizures is essential sincepharmacotherapy is highly selective for a particular type of epilepticseizure. For the treatment of epilepsy, drugs for oral administrationsuch as Phenytoin, Carbamazepine, Valproic acid, Phenobarbital,ethosuximide, Clonazepam, clobazam and Primidone have been used.Recently, the treatment of epilepsy becomes more advanced owing to thenewly developed drugs like vigabatrin, Zonisamide, Lamotrigine,topiramate, Oxcarbazepine and Gabapentine, etc. However, the results ofthe treatment of epilepsy using the said medicines are not satisfactory.The chances of controlling epilepsy with a single medicine are 60-70%and 20-25% requires co-administration of different medicines. The last10% does not show any improvement with any of the said medicines.

It would therefore be extremely beneficial if there were a way toprovide a combination therapy that simultaneously provides ameliorationor treatment of epilepsy or related seizure diseases or disorders whileat the same time addressing health issues associated with depletedphosphatidylcholine levels and increased sphingomyelin levels in cellmembranes. Accordingly, there is a long felt need for discovering newcompositions and methods that can achieve such therapeutic effects inpatients with epilepsy or related seizure diseases or disorders.

The present invention as disclosed and described herein provides methodsand compositions for a combination therapy that can be used to treat orameliorate epilepsy or related seizure diseases or disorders indicationswhile simultaneously addressing or clarifying or reducing highersphingomyelin to phosphatidylcholine ratios.

Alzheimers

Alzheimer's disease (“AD”) is a dementing disorder characterized byprogressive impairments in memory and cognition. It typically occurs inlater life, and is associated with a multiplicity of structural,chemical and functional abnormalities involving brain regions concernedwith cognition and memory. This form of dementia was first reported byAlois Alzheimer in 1907 when he described a disease of the cerebralcortex in a 51-year-old woman suffering from an inexorably progressivedementing disorder. Although other forms of dementia had been wellcharacterized at the time of Alzheimer's clinical report, his patientwas clinically and pathologically unusual, because of her relativelyyoung age and the presence of the then newly described intra-cellularinclusions which have subsequently come to be known as neurofibrillarytangles (NFTs). In recognition of this unique combination of clinicaland pathological features, the term “Alzheimer's Disease (AD)”subsequently came into common usage.

Alzheimer's disease is the most common form of dementia. As of December2013, this number is reported to be 36 million-plus worldwide. Theprevalence of Alzheimer's is thought to reach approximately 107 millionpeople by 2050. The cause and progression of Alzheimer's disease are notwell understood. The progressive formation of amyloid plaques andvascular deposits of amyloid .beta.-peptide has long been considered thepathological hallmark of Alzheimer's disease. Only a few medicationshave currently been approved by FDA for treating the cognitivemanifestations of AD, but none has indication of delaying or halting theprogression of the disease.

In Alzheimer's disease (AD), the abnormal cleavage of beta amyloidprotein precursor from the intracellular membrane often produces aprotein A_(β)1-42 which is incompletely removed by normal clearanceprocesses. It has been reported that soluble β amyloid oligomers arehighly neurotoxic. Moreover, over time, this soluble protein assemblageis deposited as a β amyloid protein A_(β) plaque within brain tissue,leading to the local destruction of neurons. The A_(β) plaque depositionis also believed to provoke an inflammatory response by microglia andmacrophages, which recognize the plaque as a foreign body. These cellsare believed to respond to the plaque deposition by releasingproinflammatory cytokines and reactive oxygen species (ROS). Althoughthe inflammatory response may be provoked in an effort to clear thebrain tissue of the detrimental plaque, it is now believed that thisinflammation also injures local neuronal tissue, thereby exacerbatingAD. Soluble oligomers of β amyloid or “ADDLs” are a neurotoxic speciesimplicated in AD pathogenesis. Yang, J. Biol. Chem., 280, 7, Feb. 18,2005, 5892-5901.

Alzheimer's disease (AD) is characterized by the extracellularaccumulation of amyloid plaques in the brain composed of the 40 or 42amino acid A_(β) peptide. This extracellular accumulation of the A_(β)42 peptide is the hallmark pathology of the disease state and thereforethought to be the most important player in the cause of Alzheimer'sdisease. While another common lesion of the Alzheimer's disease brain isthe presence of intracellular neurofibrillary tangles made up ofabnormally phosphorylated tau, a microtubule-associated protein,currently, most evidence suggests that A_(β) plays the central role inthe pathogenesis of the disease. Nevertheless, the etiology ofAlzheimer's disease is still poorly understood.

Recent advances in molecular genetics has suggested several geneticlinks to Alzheimer's disease including mutations in the amyloidprecursor protein (APP), the presenilin 1 protein, .alpha.-2macroglobulin (A2M), nicastrin, and APOE.epsilon.4. The chromosomal“hotspot” for late onset Alzheimer's disease (>65 years of onset, LOAD)has been mapped to 10 q. In contrast, the genetic loci for familialearly onset Alzheimer's disease (<65 years of onset, EOAD) mapsspecifically to APP mutations at the .gamma.-secretase site or mutationsin the presenilin 1 gene known to affect y-secretase activity. It isimportant to distinguish the difference between the genes linked to LOADand EOAD. Most, if not all of the EOAD mutations found in presenilin,nicastrin, or the APP y-cleavage site, are linked to y-secretasecleavage. On the other hand, the genes linked to LOAD have no commonlink to Alzheimer's except for their ability to alter A_(β) secretionfrom cells or clearance in the brain. Therefore, it seems clear thatEOAD is caused by a specific defect in the y-secretase activity, whilethe specific defect(s) in LOAD is still not clear.

The A_(β) peptide is generated by the endoproteolytic cleavage of theamyloid precursor protein (APP), a large type I transmembrane protein.The two enzymes that cleave APP in the amylogenic pathway are called theβ- and .gamma.-secretases which cleave APP from the N- and C-termini,respectively. In this pathway, the β-secretase (BACE) is the ratelimiting enzyme in the cleavage of APP, producing a sAPP-.beta. fragmentthat is secreted from the cell and a C99 fragment that is left in themembrane. The C99 fragment is the substrate for the .gamma.-secretase(GACE) which cleaves C99 to produce A β and a C99 “stub” that seems tofunction in a complex with Tip60 and Fe65 which derepresses a gene inthe NF.kappa.-B pathway through IL-1.beta., KAI1 (a tetraspanin cellsurface molecule). The genetic, biochemical, and molecular evidence forAlzheimer's suggests LOAD is likely to be polygenic and involve one ormore genetic defects, familial and/or spontaneous.

In spite of the many research investigations and diverse studiesundertaken to date, present clinical evaluations still cannot establishan unequivocal diagnosis of Alzheimer's disease. To the contrary, theonly presently known means for positively proving and demonstratingAlzheimer's disease in a patient can only be achieved by a brain biopsyor a postmortem examination to assess and determine the presence of NFTsand senile (amyloid) plaques in brain tissue. Instead, a set ofpsychological criteria for the diagnosis of probable Alzheimer's diseasehas been described, and includes the presence of a dementia syndromewith defects in two or more areas of cognition, and progressiveworsening of memory and other cognitive function over time. However, bythe time these psychological changes may be observed, significantirreversible neuronal damage has already occurred.

Furthermore, only a limited number of pharmacological agents heretoforehave been identified as effective in treating symptoms of Alzheimer'sdisease in a person suffering therefrom. The most prominent of thesetoday are tacrine and donepezil hydrochloride, which are cholinesteraseinhibitors active in the brain. These drugs do not slow the progress ofthe disease. Furthermore no compound has been established as effectivein blocking the development or progression of Alzheimer's diseasealthough a number of compounds, including estrogen, ibuprofen,selegiline, are thought to possibly have this capability and are beinginvestigated for therapeutic use for this purpose.

It is therefore clear that there has been and remains today a longstanding need for compositions and methods to treat Alzheimer's diseasein a living human subject before the disease has manifested far enoughto produce psychological changes, thereby allowing earlier and moreeffective therapeutic intervention. It would therefore be extremelybeneficial if there were a way to provide a combination therapy thatsimultaneously provides amelioration or treatment of Alzheimer's diseaseor related diseases or disorder while at the same time simultaneouslyaddressing other health issues related to depletion ofphosphatidylcholine levels and increased sphingomyelin levels in cellmembranes. Accordingly, there is a long felt need for discovering newcompositions and methods that can achieve such therapeutic effects inpatients with Alzheimer's disease or related disorders or diseases.

The present invention as disclosed and described herein provides methodsand compositions for a combination therapy that can be used to treat orameliorate Alzheimer's disease or related diseases or disorder whilesimultaneously addressing or clarifying or reducing higher sphingomyelinto phosphatidylcholine ratios.

Atherosclerosis

Over 50 million Americans have cardiovascular problems, and many othercountries face high and increasing rates of cardiovascular disease. Itis the number one cause of death and disability in the United States andmost European countries. By the time that heart problems are detected,the underlying cause, atherosclerosis, is usually quite advanced, havingprogressed for decades.

Atherosclerosis is a polygenic complex disease of mammals characterizedby the deposits or plaques of lipids and other blood derivatives in thearterial walls (aorta, coronary arteries, carotid arteries). Theseplaques can be calcified to a greater or lesser extent according to theprogression of the process. They are also associated with theaccumulation of fatty deposits consisting mainly of cholesterol estersin the arteries. Cholesterol accumulates in the foam cells of thearterial wall, thereby narrowing the lumen and decreasing the flow ofblood. This is accompanied by a thickening of the arterial wall, withhypertrophy of the smooth muscle, the appearance of foam cells and theaccumulation of the fibrous tissue. Hypercholesterolemia can thereforeresult in very serious cardiovascular pathologies such as infarction,peripheral vascular disease, stroke, sudden death, cardiacdecompensation, cerebral vascular accidents and the like.

The cholesterol is carried in the blood by various lipoproteinsincluding the low-density lipoproteins (LDL) and the high-densitylipoproteins (HDL). The LDL is synthesized in the liver and makes itpossible to supply the peripheral tissues with cholesterol. In contrast,the HDL captures cholesterol molecules from the peripheral tissues andtransports them to the liver where they are converted to bile acids andexcreted. The development of atherosclerosis and the risk of coronaryheart disease (CHD) inversely correlate to the levels of HDL in theserum. Gordon et al. (1989) N. Engl. J. Med. 1989 Nov. 9: 321: 1311;Goldbourt et al. (1997) Thromb Vasc. Biol. 17: 107. Low HDL cholesterolsoften occur in the context of central obesity, diabetes and otherfeatures of the metabolic syndrome. Goldbourt et al., supra. It has beensuggested that low HDL cholesterol levels are associated with anincreased risk of CHD, while high concentrations of HDL have aprotective effect against the development of premature atherosclerosis.Gordon et al. (1986) Circulation 74: 1217. Studies demonstrated that therisk for developing clinical atherosclerosis in men drops 3% with a 1%increase in the concentration of HDL in plasma. Gordon et al. (1989) N.Engl. J. Med. 321: 1311. It has been established that concentrations ofLDL cholesterol can be reduced by treatment with statins, inhibitors ofthe cholesterols biosynthesis enzyme 3-hydroxyl-3-methylglutarylCoenzyme A reductase and thereby this treatment has been used as asuccessful approach for reducing the risk for atherosclerosis where theprimary indication is high LDL level. However, it remains unclearwhether statins are beneficial for patients whose primary lipidabnormality is low HDL cholesterol.

Angina pectoris is a severe constricting pain in the chest, oftenradiating from the precordium to the left shoulder and down the leftarm. Often angina pectoris is due to ischemia of the heart and isusually caused by coronary disease.

Currently the treatment of symptomatic angina pectoris variessignificantly from country to country. In the U.S., patients who presentwith symptomatic, stable angina pectoris are frequently treated withsurgical procedures or PTCA. Patients who undergo PTCA or other surgicalprocedures designed to treat angina pectoris frequently experiencecomplications such as restenosis. This restenosis may be manifestedeither as a short term proliferative response to angioplasty-inducedtrauma or as long term progression of the atherosclerotic process inboth graft vessels and angioplastied segments.

The symptomatic management of angina pectoris involves the use of anumber of drugs, frequently as a combination of two or more of thefollowing classes: beta blockers, nitrates and calcium channel blockers.Most, if not all, of these patients require therapy with a lipidlowering agent as well. The National Cholesterol Education

Hypertension frequently coexists with hyperlipidemia and both areconsidered to be major risk factors for developing cardiac diseaseultimately resulting in adverse cardiac events. This clustering of riskfactors is potentially due to a common mechanism. Further, patientcompliance with the management of hypertension is generally better thanpatient compliance with hyperlipidemia. It would therefore beadvantageous for patients to have a single therapy which treats both ofthese conditions.

Coronary heart disease is a multifactorial disease in which theincidence and severity are affected by the lipid profile, the presenceof diabetes and the sex of the subject. Incidence is also affected bysmoking and left ventricular hypertrophy which is secondary tohypertension. To meaningfully reduce the risk of coronary heart disease,it is important to manage the entire risk spectrum. For example,hypertension intervention trials have failed to demonstrate fullnormalization in cardiovascular mortality due to coronary heart disease.Treatment with cholesterol synthesis inhibitors in patients with andwithout coronary artery disease reduces the risk of cardiovascularmorbidity and mortality.

Currently there is no cure for atherosclerosis. Pharmaceuticals such asStatins, Fibrates, and Hypertension medications are helpful in loweringbad cholesterol (LDL), slight reductions in arterial plaque, andimprovements in vasodilatation; all of which are symptomatic ofAtherosclerosis. Unfortunately, for some of the millions of individualsat risk or dealing with this disease, lifestyle changes (i.e. diet andexercise) and combinations of these drugs are simply not enough.

It would therefore be extremely beneficial if there were a way toprovide a combination therapy that simultaneously provides ameliorationor treatment of atherosclerosis or related coronary heart diseaseindications while at the same time simultaneously addressing otherhealth issues associated with depleted phosphatidylcholine levels andincreased sphingomyelin levels in cell membranes. Accordingly, there isa long felt need for discovering new compositions and methods that canachieve such therapeutic effects in patients with atherosclerosis orrelated coronary heart diseases.

The present invention as disclosed and described herein provides methodsand compositions for a combination therapy that can be used to treat orameliorate atherosclerosis or related coronary heart disease indicationswhile simultaneously addressing or clarifying or reducing highersphingomyelin to phosphatidylcholine ratios.

Depression

Recent estimates indicate that more than 19 million Americans over theage of 18 experience a depressive illness each year. The AmericanPsychiatric Association recognizes several types of clinical depression,including mild depression (dysthymia), major depression, and bipolardisorder (manic-depression). Major depression is defined by aconstellation of chronic symptoms that include sleep problems, appetiteproblems, anhedonia or lack of energy, feelings of worthlessness orhopelessness, difficulty concentrating, and suicidal thoughts.Approximately 9.2 million Americans suffer from major depression, andapproximately 15 percent of all people who suffer from major depressiontake their own lives. Bipolar disorder involves major depressiveepisodes alternating with high-energy periods of rash behavior, poorjudgment, and grand delusions. An estimated one percent of the Americanpopulation experiences bipolar disorder annually.

Significant advances in the treatment of depression have been made inthe past decade. Since the introduction of selective serotonin reuptakeinhibitors (SSRIs), i.e., Prozac®, many patients have been effectivelytreated with anti-depressant medication. New medications to treatdepression are introduced almost every year, and research in this areais ongoing. However, an estimated 10 to 30 percent of depressed patientstaking an anti-depressant are partially or totally resistant to thetreatment. Those who suffer from treatment-resistant depression havealmost no alternatives. Thus, there is a need to develop alternativetreatments for these patients.

Up to 10% of persons visiting a physician are afflicted with anaffective disorder (also known as behavioural disorder, mood disorder).Nonetheless, most cases remain undiagnosed or inadequately treated.Affective disorders include among others, depression, anxiety, andbipolar disorder. These diseases are well described in the literature;see, for example, Diagnostic and Statistical Manual of MentalDisorders-4th Edition Text Revision (DMS-IV-TR), American PsychiatricPress, 2000.

Depression, also known as unipolar affective disorder, is characterizedby a combination of symptoms such as lowered mood, loss of energy, lossof interest, feeling of physical illness, poor concentration, alteredappetite, altered sleep and a slowing down of physical and mentalfunctions resulting in a relentless feeling of hopelessness,helplessness, guilt, and anxiety. The primary subtypes of this diseaseare major depression, dysthymia (milder depression), and atypicaldepression. Other important forms of depression are premenstrualdysphoric disorder and seasonal affective disorder. Present treatment ofdepression consists of psychotherapy, antidepressant drugs, or acombination of both. Most anti-depressive drugs target the transport ofthe neurotransmitters serotonin and/or norepinephrine, or the activityof the enzyme monoamine oxidase. They include: Selectiveserotonin-reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline,fluvoxamine), tricyclic antidepressants (e.g., amitriptyline,imipramine, desipramine, nortriptyline), monoamine oxidase inhibitors(e.g., phenelzine, isocarboxazid, tranylcypromine), and designerantidepressants such as mirtazapine, reboxetine, nefazodone. However,all existing anti-depressive drugs possess shortcomings such as longlatency until response, high degree of non-responders, and undesirableside effects (Holsboer, Biol. Psychol. 57 (2001), 47-65). Therefore, aneed exists in the medical community for new anti-depressive drugs withdifferent mechanisms of action and improved pharmacological profile(Baldwin (2001) Hum. Psychopharmacol. Clin. Exp. 16:S93-S99; Greden(2002) J. Clin. Psychiatry 63 (Suppl 2): 3-7).

Anxiety disorders are defined by an excessive or inappropriate arousedstate characterized by feelings of apprehension, uncertainty, or fear.They are classified according to the severity and duration of theirsymptoms and specific affective characteristics. Categories include: (1)Generalized anxiety disorder, (2) panic disorder, (3) phobias, (4)obsessive-compulsive disorder, (5) post-traumatic stress disorder, and(6) separation anxiety disorder. The standard treatment for most anxietydisorders is a combination of cognitive-behavioural therapy withantidepressant medication. Additional medications includebenzodiazepines such as alprazolam, clonazepam, diazepam, lorazepam,halazepam, chlordiazepoxide, and other drugs such as buspirone,clonidine, pagoclone, risperidone, olanzapine, quetiapine, ziprasidone.Nonetheless, there are a number of unmet needs in the treatment ofanxiety disorders including the need for more effective, rapidly acting,and better tolerated medications; effective treatments for refractorydisorders; prevention of relapse; and promotion of resilience andlong-lasting response (Pollack, Psychopharmacol. Bull. 38 (Suppl 1)(2004) 31-37).

Bipolar disorder, also known as manic-depression, is characterized bymood swings between periods of mania (i.e. mood elevation includingexaggerated euphoria, irritability) and periods of depression. Bipolardisorder is classified according to the severity of the symptoms.Patients diagnosed with bipolar disorder type I suffer from manic ormixed episodes with or without major depression. In Bipolar Disordertype II, patients have episodes of hypomania and episodes of majordepression. With hypomania the symptoms of mania (euphoria orirritability) appear in milder forms and are of shorter duration. Thecurrent drugs used to treat bipolar disorders are lithium, valproate andlamotrigine, which stimulate the release of the neurotransmitterglutamate. As with antidepressive drugs, they take weeks to becomeeffective and can result in undesirable side effects, for example, highlevels of lithium in the blood can be fatal (Sachs (2003) J. Clin.Psychopharmacol. 23 (Suppl. 1):S2-S8).

Cushing's Syndromes are hormonal diseases with an estimated incidence ofapproximately 10 per 1 million persons (Meier and Biller (1997)Endocrinol Metab Clin North Am 26:741-762). Cushing's Syndromes areassociated with an increased blood concentration of cortisol(hypercortisolism) or the presence of glucocorticoid hormone over a longperiod of time. The most common underlying cause of Cushing's Syndromesare excessive production of ACTH by the pituitary gland. As mentionedabove, ACTH stimulates the growth of the adrenal glands and thesecretion of other corticosteroids. Elevated ACTH levels are most oftenproduced by pituitary adenomas. Cushing's Syndromes resulting from theproduction of ACTH in a location other than the pituitary gland is knownas ectopic Cushing's Syndromes. Examples of ectopic sites includethymoma, medullary carcinoma of the thyroid, pheochromocytoma, isletcell tumours of the pancreas and oat cell carcinoma of the lung.Symptoms of Cushing's Syndromes include weight gain, central obesity,steroid hypersecretion, elevated urinary cortisol excretion, moon face,weakness, fatigue, backache, headache, impotence, mental status changes,muscle atrophy, and increased thirst and urination. At the pituitarylevel, CRH stimulates ACTH synthesis. ACTH overproduction by pituitaryadenomas leads to excessive glucocorticoid secretion from the adrenalglands which causes endogenous Cushing's Syndromes, characterized by atypical abnormal fat deposition around the neck, thinning of the skin,osteoporosis, insulin resistance, dyslipidemia, myopathy, amenorrhea andhypertension. Fatigue, irritation, anxiety and depression are alsocommon clinical features in these patients (Orth (1995) N. Engl. J. Med.332:791-803; Dahia and Grossman (1999) Endocr. Rev. 20:136-55).

Although to date no single cause of clinical depression has beenidentified, it is now generally accepted that there is likely aneurochemical component to it. Typical treatments now often consist of acombination of psychotherapy and medication. Currently, the mostcommonly used antidepressant medications function generally to regulatebrain neurotransmitters such as dopamine, serotonin and norepinephrine.Two classes of compounds, one known as selective serotonin reuptakeinhibitors, or SSRIs, and the other known as serotonin andnorepinephrine reuptake inhibitors (SNRIs) are widely prescribed fortreatment of depression. These antidepressants, such as fluoxetine(Prozac®), sertraline (Zoloft®), venlafaxine (Effexor®) and duloxetine(Cymbalta®) have gained substantial popularity because they cause fewerside effects than earlier antidepressants, such as monoamine oxidaseinhibitors (MAOIs). Notwithstanding their improved tolerability,however, SSRIs and SNRIs still cause their share of side effects,including insomnia, nausea and sexual dysfunction. In addition to theassociated problems, a major concern with known antidepressants is thetime they take to achieve their desired effect. In most cases, it willbe a minimum of three to four weeks before a full relief of symptoms isobserved. In the case of severe depression, this delay can sometimes belife-threatening. Furthermore, only about two-thirds of patients treatedactually respond to modern antidepressants. Thus, there continues to bea need for development of new antidepressant medications that will avoidsome or all of the problems observed with those antidepressantscurrently in use. Based on a novel observation regarding theneurochemical basis for depression, the present invention fills such aneed.

It is therefore clear that there has been and remains today a longstanding need for compositions and methods to treat depression and itsrelated diseases and disorders in a living human subject before thedisease has manifested far enough to produce psychological changes,thereby allowing earlier and more effective therapeutic intervention. Itwould therefore be extremely beneficial if there were a way to provide acombination therapy that simultaneously provides amelioration ortreatment of depression or related diseases or disorder while at thesame time simultaneously addressing other health issues associated withdepleted phosphatidylcholine levels and increased sphingomyelin levelsin cell membranes. Accordingly, there is a long felt need fordiscovering new compositions and methods that can achieve suchtherapeutic effects in patients with depression or related disorders ordiseases.

The present invention as disclosed and described herein provides methodsand compositions for a combination therapy that can be used to treat orameliorate symptoms of diseases related to seizures, Alzheimers,depression, and atherosclerosis while simultaneously addressing orclarifying or reducing higher sphingomyelin to phosphatidylcholineratios in the cell membrane.

II. SUMMARY OF THE INVENTION

The present invention is directed to compositions and methods fortreating symptoms of disease related to an imbalance of essential fattyacids including seizure, depression, Alzheimer disease, andatherosclerosis, in a subject in need thereof.

In its broadest aspect, a pharmaceutical composition for cannabinoidcombination therapy is provided comprising: (a) a therapeuticallyeffective amount of a first composition comprising a balanced PCcomposition; and (b) a therapeutically effective amount of a secondcomposition comprising one or more cannabinoids, a natural or syntheticderivative thereof, or a salt thereof; wherein said first compositionand said second composition are each administered together with apharmaceutically acceptable carrier or diluent.

In one embodiment of the present invention, the balanced PC compositioncomprises Phosphotidylcholine (PC), Phosphotidylethanolamine (PE),Phosphatidyl inositol (PI), Phosphatidic Acid (PA), Phosphatidylglycerol(PG), Essential Fatty Acids C18.2 (omega 6) (linoleic acid), C18.3(omega 3)(alpha linolenic acid)(in an approximate 4:1 ratio), or anycombination thereof.

In another embodiment of the present invention, the balanced PCcomposition comprises phospholipids derived from a variety of plant andanimal sources.

In one embodiment, a pharmaceutical composition for combination therapyis provided comprising: (a) a therapeutically effective amount of afirst composition comprising a balanced PC composition; and (b) atherapeutically effective amount of a second composition comprising oneor more cannabinoids, an isolated natural or synthetic derivativethereof, or salt thereof; wherein said first composition and said secondcomposition are each administered together with a pharmaceuticallyacceptable carrier or diluent.

In another aspect, a pharmaceutical composition is provided for theprevention, amelioration and/or treatment of symptoms of diseasesrelated to impairment of development and activities of cells andtissues, wherein the pharmaceutical composition comprises at least twocompositions, a therapeutically effective amount of a first compositioncomprising a balanced PC composition and a therapeutically effectiveamount of a second composition comprising one or more cannabinoids, anisolated natural or synthetic derivative thereof, or salt thereof, in asuitable carrier or diluent.

Thus, in one embodiment, this invention is directed to compositioncomprising a first composition for use with a second composition forachieving an anti-seizure effect in a subject, wherein said firstcomposition comprises a therapeutically effective amount of a balancedPC composition; and (b) a therapeutically effective amount of a secondcomposition comprising one or more cannabinoids, a natural or syntheticderivative thereof, or a salt thereof, wherein said first compositionand said second composition are each optionally and independentlyadministered together with a pharmaceutically acceptable carrier ordiluent.

In certain embodiments, said anti-seizure effect is manifested by aslowing of the progression of one or more symptoms or effects ofseizures including, for example, and not by way of limitation, déjà vu,jamais vu, smell, sound, taste, visual loss or blurring, racingthoughts, stomach feelings, tingling feeling, sudden feelings of fear oranxiousness, nausea, dizziness, numbness, changes in vision, blackout,confusion, uncontrollable muscle spasms, drooling or frothing at themouth, falling, taste strange taste sensations (aura), clenching teeth,sudden, rapid eye movements, grunting, incontinence, sudden moodchanges, deafness/sounds, electric shock feeling, loss of consciousness,spacing out, out of body experience, visual loss or blurring,fear/panic, chewing movements, convulsion, difficulty talking, eyelidfluttering, eyes rolling up, falling down, foot stomping, hand waving,inability to move, lip smacking, making sounds, shaking, staring,stiffening, swallowing, sweating, teeth clenching/grinding, tonguebiting, tremors, twitching movements, breathing difficulty, heartracing, after-seizure symptoms (postictal), memory loss, writingdifficulty, depression, sadness, fear, frustration, shame/embarrassment,bruising, injuries, sleeping, exhaustion, headache, nausea, pain,thirst, weakness, urge to urinate/defecate, or any combination thereof.

In one embodiment, the therapeutically effective amount of a firstcomposition comprising a balanced PC composition and the therapeuticallyeffective amount of a second composition comprising one or morecannabinoids, an isolated natural or synthetic derivative thereof, orsalt thereof compositions are formulated in one or different solutions,are either singularly or both administered in a time-released manner,are either singularly or both administered in a dry formulation, liquidformulation, or are either singularly or both administered parenteraly,orally, transdermally, intranasally, intravenously, or using otherroutes of administration as described infra.

In one embodiment, the therapeutically effective amount of a firstcomposition comprising a balanced PC composition and the therapeuticallyeffective amount of a second composition comprising one or morecannabinoids, an isolated natural or synthetic derivative thereof, orsalt thereof, are administered contemporaneously or are administered atdifferent time intervals.

In another embodiment, the therapeutically effective amount of a firstcomposition comprising a balanced PC composition is administered in anyorder or is administered both prior to and after the therapeuticallyeffective amount of a second composition comprising one or morecannabinoids, an isolated natural or synthetic derivative thereof, orsalt thereof.

In a preferred embodiment, the therapeutically effective amount of afirst composition comprising a balanced PC composition and thetherapeutically effective amount of a second composition comprising oneor more cannabinoids, an isolated natural or synthetic derivativethereof, or salt thereof, are administered to a subject in need thereofin a single dose semi-liquid packet.

In another aspect of the present invention, methods are provided fortreating a subject at risk for developing symptoms of diseases relatedto an imbalance of essential fatty acids and impairment of developmentand activities of cells and tissues. Such diseases and disordersaccording to the invention disclosed and claimed herein include seizure,depression, dementia, Alzheimer's disease, and atherosclerosis. In orderto delay the onset of the one or more of the underlying symptoms relatedto the aforementioned diseases, the prevention, treatment and/oramelioration of symptoms need not be complete, so long as at least onesymptom of the disease is prevented, treated and/or ameliorated.

In one embodiment, this invention is also directed to a method fortreating a subject which has been diagnosed as suffering from seizure ora related disease or disorder and who is in need of therapeutictreatment comprising administering to said subject (a) a therapeuticallyeffective amount of a first composition comprising a balanced PCcomposition; and (b) a therapeutically effective amount of a secondcomposition comprising one or more cannabinoids, a natural or syntheticderivative thereof, or a salt thereof; wherein said first compositionand said second composition are each optionally and independentlyadministered together with a pharmaceutically acceptable carrier ordiluent, and wherein said therapeutic treatment is prevention, treatmentor amelioration of one or more symptoms of seizure or a related diseaseor disorder.

In yet another aspect, the present invention is directed to compositionsand methods for treating dementia, Alzheimer's disease and relateddiseases and disorders in a subject in need thereof as disclosed inApplicant's co-pending U.S. Provisional Application No. 61/969,068,filed Mar. 21, 2014, entitled Compositions and Methods for TreatingAlzheimer's Disease and assigned to BodyBio Inc., the entire contents ofwhich are incorporated herein by reference.

Thus, in one embodiment, this invention is directed to compositioncomprising a first composition for use with a second composition forachieving an anti-Alzheimer's disease effect in a subject, wherein saidfirst composition comprises a therapeutically effective amount of afirst composition comprising a balanced PC composition; and (b) atherapeutically effective amount of a second composition comprising oneor more cannabinoids, a natural or synthetic derivative thereof, or asalt thereof, wherein said first composition and said second compositionare each optionally and independently administered together with apharmaceutically acceptable carrier or diluent.

In certain embodiments, said anti-Alzheimer's disease effect ismanifested by a reduction or amelioration of the progression of signs orsymptoms associated with Alzheimers disease including impairment ofshort term memory, impairment of abstract thinking, impairment ofjudgment, impairment of language skills, dementia, and mood changes, orany combination thereof.

In another aspect of the present invention, methods are provided fortreating a subject at risk for developing symptoms of diseases relatedto impairment of development and activities of cells and tissues inorder to delay the onset of the one or more of the aforementionedunderlying symptoms related to Alzheimer's disease. The prevention,treatment and/or amelioration of one or more of the aforementionedsymptoms related to Alzheimer's disease need not be complete, so long asat least one symptom of the disease is prevented, treated orameliorated.

In one embodiment, this invention is also directed to a method fortreating a subject which has been diagnosed as suffering fromAlzheimer's disease and who is in need of therapeutic treatmentcomprising administering to said mammal (a) a therapeutically effectiveamount of a first composition comprising a balanced PC composition; and(b) a therapeutically effective amount of a second compositioncomprising one or more cannabinoids, a natural or synthetic derivativethereof, or a salt thereof; wherein said first composition and saidsecond composition are each optionally and independently administeredtogether with a pharmaceutically acceptable carrier or diluent, andwherein said therapeutic treatment is prevention, treatment oramelioration of one or more signs or symptoms of Alzheimer's disease.

In certain embodiments, the one or more signs or symptoms of Alzheimer'sdisease that are reduced or ameliorated include impairment of short termmemory, impairment of abstract thinking, impairment of judgment,impairment of language skills, dementia, and mood changes, or anycombination thereof.

In yet another aspect, the present invention is directed to compositionsand methods for treating atherosclerosis and related diseases anddisorders in a subject in need thereof as disclosed in Applicant'sco-pending U.S. Provisional Application No. 61/969,063, filed Mar. 21,2014, entitled Compositions and Methods for Treating Atherosclerosis,and assigned to BodyBio Inc., the entire contents of which areincorporated herein by reference.

Thus, in one embodiment, this invention is directed to compositioncomprising a first composition for use with a second composition forachieving an anti-atherosclerotic effect in a subject, wherein saidfirst composition comprises a therapeutically effective amount of abalanced PC composition; and (b) a therapeutically effective amount of asecond composition comprising one or more cannabinoids, a natural orsynthetic derivative thereof, or a salt thereof, wherein said firstcomposition and said second composition are each optionally andindependently administered together with a pharmaceutically acceptablecarrier or diluent.

In certain embodiments, said antiatherosclerotic effect is manifested bya slowing of the progression of atherosclerotic plaques, wherein saidprogression of atherosclerotic plaques is slowed in coronary arteries,carotid arteries, or the peripheral arterial system or any combinationthereof

In another embodiment, the antiatherosclerotic effect is manifested by aregression of atherosclerotic plaques, wherein the regression ofatherosclerotic plaques occurs in coronary arteries, carotid arteries,or the peripheral arterial system, or any combination thereof.

In another aspect of the present invention, methods are provided fortreating a subject at risk for developing symptoms of diseases relatedto impairment of development and activities of cells and tissues inorder to delay the onset of the one or more of the aforementionedunderlying symptoms related to atherosclerosis. The prevention,treatment and/or amelioration of one or more of the aforementionedsymptoms related to seizure need not be complete, so long as at leastone symptom of the disease is prevented, treated or ameliorated.

In one embodiment, this invention is also directed to a method fortreating a subject which has been diagnosed as suffering fromatherosclerosis and who is in need of therapeutic treatment comprisingadministering to said mammal (a) a therapeutically effective amount of afirst composition comprising a balanced PC composition; and (b) atherapeutically effective amount of a second composition comprising oneor more cannabinoids, a natural or synthetic derivative thereof, or asalt thereof; wherein said first composition and said second compositionare each optionally and independently administered together with apharmaceutically acceptable carrier or diluent, and wherein saidtherapeutic treatment is prevention, treatment or amelioration of one ormore symptoms of atherosclerosis.

In another aspect, the present invention is directed to compositions andmethods for treating depression and related diseases and disorders in asubject in need thereof as disclosed in Applicant's co-pending U.S.Provisional Application No. 61/969,069, filed Mar. 21, 2014, entitledCompositions and Methods for Treating Depression, and assigned toBodyBio Inc., the entire contents of which are incorporated herein byreference.

Thus, in one embodiment, this invention is directed to compositioncomprising a first composition for use with a second composition forachieving an anti-depression effect in a subject, wherein said firstcomposition comprises a therapeutically effective amount of a balancedPC composition; and (b) a therapeutically effective amount of a secondcomposition comprising one or more cannabinoids, a natural or syntheticderivative thereof, or a salt thereof, wherein said first compositionand said second composition are each optionally and independentlyadministered together with a pharmaceutically acceptable carrier ordiluent.

In certain embodiments, said anti-depression effect is manifested by areduction or amelioration of the progression of signs or symptomsassociated with depression including depressed mood, irritability,instability of mood, and/or changes in mood, stress, hormonal moodswings (e.g., during pregnancy, during post-partum, during puberty,during menopause or are a result of a Premenstrual Dysphoric Disorder orrelated condition), impairment of short term memory, impairment ofabstract thinking, impairment of judgment, impairment of languageskills, and depression-related dementia, or any combination thereof.

In another aspect of the present invention, methods are provided fortreating a subject at risk for developing symptoms of diseases relatedto impairment of development and activities of cells and tissues inorder to delay the onset of the one or more of the aforementionedunderlying symptoms related to depression. The prevention, treatmentand/or amelioration of one or more of the aforementioned symptomsrelated to depression need not be complete, so long as at least onesymptom of the disease is prevented, treated or ameliorated.

In one embodiment, this invention is also directed to a method fortreating a subject which has been diagnosed as suffering from depressionor a related disease or disorder and who is in need of therapeutictreatment comprising administering to said subject (a) a therapeuticallyeffective amount of a first composition comprising a balanced PCcomposition; and (b) a therapeutically effective amount of a secondcomposition comprising one or more cannabinoids, a natural or syntheticderivative thereof, or a salt thereof; wherein said first compositionand said second composition are each optionally and independentlyadministered together with a pharmaceutically acceptable carrier ordiluent, and wherein said therapeutic treatment is prevention, treatmentor amelioration of one or more signs or symptoms of depression.

In certain embodiments, the one or more signs or symptoms of depressionthat are reduced or ameliorated include depressed mood, irritability,instability of mood, and/or changes in mood, stress, hormonal moodswings (e.g., during pregnancy, during post-partum, during puberty,during menopause or are a result of a Premenstrual Dysphoric Disorder orrelated condition), impairment of short term memory, impairment ofabstract thinking, impairment of judgment, impairment of languageskills, and depression-related dementia, or any combination thereof.

In another embodiment, this invention is directed to compositioncomprising a first composition for use with a second composition forachieving an anti-seizure effect, an anti-alzheimer's effect, ananti-atherosclerosis effect, anti-depression effect in a subject, or anycombination thereof, wherein said first composition comprises atherapeutically effective amount of a balanced PC composition; and (b) atherapeutically effective amount of a second composition comprising oneor more cannabinoids, a natural or synthetic derivative thereof, or asalt thereof, wherein said first composition and said second compositionare each optionally and independently administered together with apharmaceutically acceptable carrier or diluent.

In certain embodiments, said anti-seizure effect, anti-alzheimer'seffect, anti-atherosclerosis effect, anti-depression effect, or anycombination thereof, is manifested by a reduction or amelioration of theprogression of the signs or symptoms associated with seizure,alzheimer's, atherosclerosis, depression, as described supra, or anycombination thereof.

In another embodiment, this invention is also directed to a method fortreating a subject which has been diagnosed as suffering from seizure,alzheimer's, atherosclerosis, depression or a related disease ordisorder, or any combination thereof, and who is in need of therapeutictreatment comprising administering to said subject (a) a therapeuticallyeffective amount of a first composition comprising a balanced PCcomposition; and (b) a therapeutically effective amount of a secondcomposition comprising one or more cannabinoids, a natural or syntheticderivative thereof, or a salt thereof; wherein said first compositionand said second composition are each optionally and independentlyadministered together with a pharmaceutically acceptable carrier ordiluent, and wherein said therapeutic treatment is prevention, treatmentor amelioration of one or more signs or symptoms of seizure, alzheimer'satherosclerosis, depression, as recited supra, or any combinationthereof.

In each of the aforementioned methods, the one or more cannabinoidscomprise natural or synthetic variants of cannabinoids and include forexample and not by way of limitation, those Cannabis-DerivedCannabinoids comprising Cannabinoids obtained from Cannabis indica plantincluding, for example, and not by way of limitation, Cannabidiol (CBD),Cannabinol (CBN), Cannabigerol (CBG); Cannabichromene (CBC);Cannabicyclol (CBL); Cannabivarin (CBV); Tetrahydrocannabivarin (THCV);Cannabidivarin (CBDV); Cannabichromevarin (CBCV); Cannabigerovarin(CBGV); Cannabigerol Monomethyl Ether (CBGM); and Tetrahydrocannabinol(THC), other Phytocannabinoids comprising those cannabinoids fromseveral other several plant species besides cannabis, including, forexample, and not by way of limitation, Echinacea purpurea, Echinaceaangustifolia, Echinacea pallida, Acmella oleracea, Helichrysumumbraculigerum, and Radula marginata, as well as Synthetic Cannabinoidsincluding, for example, and not by way of limitation, Dronabinol(Marinol) (Δ9-tetrahydrocannabinol (THC)), Nabilone (Cesamet), Sativex,and Rimonabant (SR141716).

In another aspect, a kit is provided for the pharmaceutical compositioncomprising: a) a first composition comprising a balanced PC composition;b) a second composition comprising one or more cannabinoids, an isolatednatural or synthetic derivative thereof, or salt thereof; and c)instructions for the use of the first and second active compositions andthe additional constituents of the kit.

Other embodiments, objects, features and advantages will be set forth inthe detailed description of the embodiments that follows, and in partwill be apparent from the description, or may be learned by practice, ofthe claimed invention. These objects and advantages will be realized andattained by the processes and compositions particularly pointed out inthe written description and claims hereof. The foregoing Summary hasbeen made with the understanding that it is to be considered as a briefand general synopsis of some of the embodiments disclosed herein, isprovided solely for the benefit and convenience of the reader, and isnot intended to limit in any manner the scope, or range of equivalents,to which the appended claims are lawfully entitled.

III. DETAILED DESCRIPTION OF THE INVENTION

Reference now will be made in detail to embodiments of the invention. Itwill be apparent to those skilled in the art that various modificationsand variations can be made in the present invention without departingfrom the scope or spirit of the invention. For instance, featuresillustrated or described as part of one embodiment, can be used onanother embodiment to yield a still further embodiment.

In general, the present invention is directed to compositions andmethods related to a combination therapy that prevents, amelioratesand/or treats symptoms of diseases and disorders related to imbalance offatty acids and developmental imbalance and dysfunction of cells andtissues, as applied to a wide spectrum of diseases and disorders, listedinfra, through administration of a combination therapy comprising afirst composition comprising a balanced PC composition in combinationwith a second composition comprising one or more cannabinoids.

The combination therapy of the present invention has unexpectedlycompletely circumvented the known deleterious side effects associatedwith the higher dose administration of cannabinoids by co-administrationof a balanced PC composition and one or more cannabinoids, which in turnincreases the bioavailability of this drug and its adsorption andpassage through cell membranes and the blood brain barrier.

Cannabinoids such as, for example, cannabis or cannabidiol have beenshown to be effective for modulation of tissue regeneration anddevelopment. There are, however, many side effects associated withcannabis and especially to the higher dosages of cannabis. Only about 1%of cannabis is reported to pass the blood brain barrier whenadministered alone intravenously.

By reducing or preventing the one or more side effects of the use ofcannabinoids alone, the present invention provides a combination therapyof one or more cannabinoids with a balanced PC composition, wherein theoverall therapeutic benefits described infra are increased considerably.Furthermore, the reduction or prevention of the side effects ofcannabinoid use when administered in combination with a balanced PCcomposition provides an unexpected synergistic benefit.

The unexpected synergistic effects of the balanced PC compositioncannabinoid combination therapy of the present invention include, forexample, and not by way of limitation, i) reducing the oxidative stressof free radicals and increasing cellular homeostasis resulting fromsynergistically increasing the bioavailability of one or morecannabinoids; ii) inhibiting the formation of cholesteryl esters derivedfrom LDL or other synthesis and increasing efflux of cholesterol fromthe cells by decreasing available cholesterol for esterification as aresult of synergistically increasing the bioavailability of bothendogenous and exogenous cannabinoids; iii) inhibiting the progressionof atherosclerotic plaque and significantly reducing arterial plaquethrough modulation and synergistically increasing the bioavailability ofboth endogenous and exogenous cannabinoids; and iv) acting as a smoothmuscle relaxant, relaxing arterial walls (vasodilatation), loweringblood pressure, and increasing blood flow and circulation bysynergistically increasing the bioavailability of cannabinoids.

In general, a balanced PC composition of the present invention providesthe following beneficial characteristics: i) enhanced PC concentration;ii) improved solubility and stability of PC; iii) Improvedbioavailability of PC; iv) improved targeting cell membrane capabilityin vivo and hence enhanced immunological benefit (a balanced PCcomposition has an enhanced glycoprotein concentration and henceincreased capability to provide additional receptors via attachment tocell membranes in vivo); v) having a reduced concentration of integralcarbohydrates including glycolipids, galactose, etc.; vi) having areduced concentration of undesirable lipids including, for example,sphingomyelin; vii) having an improved concentration of the essentialfatty acids and a balanced ratio of linoleic acid and alpha linolenicacid (in an approximate 4:1 ratio); and viii) having a range ofbeneficial minerals and electrolytes in a specific concentration range;and xi) having an improved ability for liposome mediated-transport ofdrugs or any combination thereof. These balanced PC composition benefitssynergistically combine together with the one or more cannabinoids inthe balanced PC cannabinoid composition combination therapy utilized inthe compositions and methods of the present invention to provide one ormore of the therapeutic benefits described herein.

In one embodiment, the balanced PC composition cannabinoid compositionsand methods prepared according to the present invention provide asuspension of liposomes containing substantially morephosphatidylcholine than the available competing phosphatidyl products.

In another embodiment, the liposomes produced by the methods of thepresent invention are small unilamellar vesicles (SUVs) having sizespredominantly between 0.02 and 0.1 microns, and are composedpredominantly or exclusively of a balanced PC composition with the oneor more cannabinoids entrapped there within.

Without intending to be limited to a particular mechanism of action, itis believed that the administration of a balanced PC composition incombination with one or more exogenous cannabinoids serves tosynergistically regulate and promote the aforementioned physiologicalhomeostasis in the endocannabinoid system by leading to a decrease inthe relative sphingomyelin to phosphatidylcholine mass ratio which inturn synergistically allows the endogenous cannabinoid system tomodulate the severity and/or duration of seizure, Alzheimer's disease,atherosclerosis, and/or depression through activation of the CB1receptor.

Components of the Composition of the Combination Therapy

1. Components of Balanced PC Composition

1.1 Phosphatidylcholine

Phosphatidylcholine (PC) is the predominant phospholipid of all cellmembranes and of the circulating blood lipoproteins. Of the tens ofthousands of molecules that make up the life of a cell,Phosphatidylcholine (PC) stands apart; probably the most important oneof all. PC is the main lipid constituent of the lipoprotein particlescirculating in the blood and the preferred precursor for certainphospholipids and other biologically important molecules. PC alsoprovides antioxidant protection in vivo. In animal and human studies, PCprotected against a variety of chemical toxins and pharmaceuticaladverse effects.

Chemically, PC is a glycerophospholipid that is built on glycerol(CH2OH—CHOH—CH2OH) and substituted at all three carbons. Carbons I and 2are substituted by fatty acids and carbon 3 by phosphorylcholine.Simplistically, the PC molecule consists of a head-group(phosphorylcholine), a middle piece (glycerol), and two tails (the fattyacids, which vary). Variations in the fatty acids in the tails accountfor the great variety of PC molecular species in human tissues.

In vivo, PC is produced via two major pathways. In the predominantpathway, two fatty acids (acyl “tails”) are added to glycerol phosphate(the “middle piece”), to generate phosphatidic acid (PA) that isconverted to diacylglycerol, after which phosphocholine (the“head-group”) is added on from CDP-choline. The second, minor pathway isphosphatidylethanolamine (PE) methylation, the PEMT pathway, in whichthe phospholipid PE has three methyl groups added to its ethanolaminehead-group, thereby converting it into PC.

In one embodiment, the PC component of the balanced PC compositioncannabinoid combination therapy of the present invention may be derivedfrom any and all lecithin-based raw materials, for which thephosphatides have been rendered water soluble by one of the manypreviously published fluidizing methods, for example, Short, U.S. Pat.No. 4,221,731 1980, Flider, U.S. Pat. No. 4,399,224 1983, the entiredisclosures of each of which are specifically incorporated by referenceherein, and those commercial suppliers of raw lecithin such as, forexample, and not by way of limitation, Archer Daniels Midland (ADM),Cargill, Bunge, Solae, American Lecithin, or any plant lecithin oranimal lecithin including for example, and not by way of limitation,egg, or any combination thereof.

In another embodiment, the PC component of the balanced PC compositioncannabinoid combination therapy comprises phosphatidylcholine derivedfrom soy.

In another embodiment, the first composition of the present invention isa balanced PC composition which is specifically available from BodyBioInc. (referred to hereinafter as “BodyBio PC”, “BodyBio balanced PC” or“balanced PC”). The concentration of PC in BodyBio PC for administrationranges from about 100 mg to about 10,000 mg. In one embodiment, theconcentration range of PC is from about 200 mg to about 5000 mg. Inanother embodiment, the concentration range of PC is from about 300 mgto about 3000 mg. In a preferred embodiment of the invention, theconcentration range of PC is from about 500 mg to about 1000 mg.

In one embodiment, the total amount of phospholipids in BodyBio PC isabout 61%, which is about 9% higher than competitive PC products (i.e.,approximately 61% versus about 52%). In one embodiment, total amount ofphosphatidylcholine in BodyBio PC is approximately 29%, which is about11-16% higher than competitive PC products such as for example, and notby way of limitation, that found with lecithin supplied by Dupont andADM (i.e., about 29% versus about 18%). The percentages recited hereinfor the differences between BodyBio PC and competitive PC products areapproximations only and are thus intended to include percentages thatare up to 10% lower or 10% higher than the recited value, and allinteger values there between.

In one embodiment, for example, and not by way of limitation, the fattyacids and phospholipid concentration in the intermediatephosphatidylcholine compound is presented below (including anycombinations thereof). These percentage values provided below representa non-limiting example of fatty acid content and of the variousphospholipids found in the composition. The percentages recited hereinare approximate and are intended to include percentages that are up to10% lower or 10% higher than the recited value.

Fatty Acid Content: C16.0 16.1% C16.1 0.1% C18.0 4.1% C18.1 10.0%

C18.2 55.30% (omega 6)C18.3 14.0% (omega 3)

C22.0 0.4% Phospholipids:

Phosphotidylcholine (PC): about 29%Phosphotidylethanolamine (PE): about 16%Phosphatidyl inositol (PI): about 9%Phosphatidic Acid (PA): about 4%Phosphatidylglycerol (PG): about 1%Total Phospholipids about 61%

BodyBio PC contains a ratio of about 4 parts linoleic acid to about 1part alpha linolenic acid. Most lecithin produced from soy has anessential fatty acid ratio of approximately 10-12:1.

BodyBio balanced PC is composed of phosphatides that are amphiphilic andautomatically form bilipid membranes (liposomes) or unilipid membranes(micelles). Lecithin may contain the desired health providingphosphatides, however, in contrast to BodyBio balanced PC, thephospholipids derived from lecithin are generally oil based, which makethem only suitable as an emulsifying agent for foods and cosmetics.Oil-based phosphatides are not amphiphilic, they have lost the necessaryhydrophobic reaction to form a liposomal membrane and thus are incapableof integration into cell membranes and add to internal nutritionalsupport system.

The increased level of available phospholipids in the balanced PCcomposition of the present invention is a significant improvement overthe competitive PC products. The balanced PC compositions of the presentinvention have the unique advantage of containing phosphatidylethanolamine (PE), which has recently been found to be a necessaryphospholipid in the membranes of mitochondria for the production ofenergy.

Thus, in one embodiment of the present invention, the balanced PCcomposition of the present invention comprises Phosphotidylcholine (PC),Phosphotidylethanolamine (PE), Phosphatidyl inositol (PI), PhosphatidicAcid (PA), Essential Fatty Acids comprising C18.2 (omega 6) (linoleicacid) C18.3 (omega 3)(alpha linolenic acid) (in an approximate 4:1 ratiofor the essential fatty acids or EFAs), or any combination thereof.

Mitochondrial membranes are enriched in phospholipids and proteins thatare required for mitochondrial biogenesis and for maintenance ofmitochondrial morphology and the tubular network. The two non-bilayerforming mitochondrial phospholipids cardiolipin (CL) (CL3) andphosphatidylethanolamine (PE) are required to maintain tubularmitochondrial morphology and are known to have overlapping functions inmitochondrial fusion. Although cells lacking CL or mitochondrial PE areviable, the loss of both phospholipids is lethal.

2. Cannabinoids for Use in the Second Composition

The compositions of the combination therapy of the present inventioninclude as the second composition one or more cannabinoids, an isolatednatural or synthetic derivative thereof, or salt thereof. Cannabinoidsare a heteromorphic group of chemicals that act on cannabinoid receptorson cells that repress neurotransmitter release in the brain. Thesereceptor proteins include the endocannabinoids (produced naturally inthe body by humans and animals), the phytocannabinoids (found incannabis and some other plants), and synthetic cannabinoids(manufactured chemically). The most notable cannabinoid is thephytocannabinoid Δ9-tetrahydrocannabinol (THC), the primary psychoactivecompound of cannabis. Cannabidiol (CBD) is another major constituent ofthe plant, representing up to 40% in extracts of the plant resin. Thereare at least 85 different cannabinoids isolated from cannabis,exhibiting varied effects. Synthetic cannabinoids encompass a variety ofdistinct chemical classes: the classical cannabinoids structurallyrelated to THC, the nonclassical cannabinoids (cannabimimetics)including the aminoalkylindoles, 1, 5-diarylpyrazoles, quinolines, andarylsulphonamides, as well as eicosanoids related to theendocannabinoids.

Cannabinoids according to this invention can either be exogenic orendogenic in origin. Exogenic cannabinoids can be both natural, (i.e.Phytocannabinoids derived from the cannabis plant itself) and synthetic(i.e. Marinol, Sativex, etc.) These exogenic cannabinoids can be bothbinding, aka agonists (i.e. THC the main psychoactive compound) andnon-binding, aka antagonists (i.e., the non-psychoactive cannabinoidsCBD, CBN, CBG, etc.) to endogenous cannabinoid receptors in vivo.Endogenic cannabinoids (i.e. Anandamide, 2-AG, etc.) and endogenousreceptors sites (i.e. CB1 and CB2) are found throughout the body andregulate homeostasis in a wide variety of physiological and neurologicalfunctions from birth till death. Endocannabinoids are found in the humanplacenta and even breast milk and are essential to all the body'sregulatory functions.

Endocannabinoids are lipid derived mediators which can be activated,stored, and synthesized from the cell membranes phospholipid's bilayerthrough multiple pathways, although complete understanding of thetransport system needs further study. Endocannabinoid production can beincreased by the introduction of extracellular stimuli (i.e., theingestion or introduction of exogenic cannabinoids). The phospholipidbilayer, along with its many other functions, plays a central role inthe Endocannabinoid System. A healthy phospholipid bilayer is thereforeessential to a healthy Endocannabinoid system (ECS) and vice versa: thephospholipid bilayer and the ECS work together synergistically toregulate and promote physiological homeostasis. The ECS and itsregulatory processes are extremely sensitive to the quality andstructure of the phospholipid bilayer. This relationship and thesynergistic effects thereto are enhanced and exploited by using thebalanced PC cannabinoid combination therapeutic treatments of theinvention as described herein to achieve a further synergistic effectwhich is much greater than the additive value expected by combination ofa balanced PC composition and cannabinoids.

What follows is a non-limiting listing of the cannabinoids that may beused in the combination therapy compositions and methods of the presentinvention.

2.1 Cannabis-Derived Cannabinoids

2.1.1 Cannabis, Sativa, Indica Plant Ruderalis and Hybrids Thereof

The Cannabis plant, a genus of dioeciously flowering plants, has beendivided into three distinct species: Cannabis Sativa, Cannabis Indica,and Cannabis Ruderalis. Phytocannabinoids (i.e., THC, CBD, CBN, CBG,etc.) can be extracted through various methods and have been used inmedicinal compositions for thousands of years by many different culturesaround the world for a wide range of symptoms and ailments.

The classical cannabinoids are concentrated in a viscous resin producedin structures known as glandular trichomes. At least 85 differentcannabinoids have been isolated from the Cannabis plant. The beststudied cannabinoids include tetrahydrocannabinol (THC), cannabidiol(CBD) and cannabinol (CBN).

Despite the huge variety of marijuana available, almost all ultimatelycome from two cannabis family species. These two essential species areknown as Cannabis sativa and Cannabis Indica and they differfundamentally in their chemical composition and medical applications.Cannabis Ruderalis a.k.a. industrial hemp is the third species andinterest in this species is gaining momentum at the moment because it ishigh in the non-psychoactive cannabinoid CBD and contains only traceamounts of 1% or less the psychoactive cannabinoid.

2.2.1 Types of Cannabinoids

All classes derive from cannabigerol-type compounds and differ mainly inthe way this precursor is cyclized. The classical cannabinoids arederived from their respective 2-carboxylic acids (2-COOH) bydecarboxylation (catalyzed by heat, light, or alkaline conditions)include the following: CBG (Cannabigerol); CBC (Cannabichromene); CBL(Cannabicyclol); CBV (Cannabivarin); THCV (Tetrahydrocannabivarin); CBDV(Cannabidivarin); CBCV (Cannabichromevarin); CBGV (Cannabigerovarin);CBGM (Cannabigerol Monomethyl Ether); and Tetrahydrocannabinol

2.2.2 Tetrahydrocannabinol

Tetrahydrocannabinol (THC) is the primary psychoactive component of theCannabis plant. Delta-9-tetrahydrocannabinol (Δ9-THC, THC) anddelta-8-tetrahydrocannabinol (Δ8-THC) mimic the action of anandamide, aneurotransmitter produced naturally in the body. These two THC's producethe effects associated with cannabis by binding to the CB1 cannabinoidreceptors in the brain. THC appears to ease moderate pain (analgesic)and to be neuroprotective. Studies show THC reduces neuroinflammationand stimulates neurogenesis. THC has approximately equal affinity forthe CB1 and CB2 receptors. Its effects are perceived to be morecerebral.

2.2.2.1 Sources of THC

The Indica and Sativa subspecies differ in their medicinal properties.Sativa strains produce more of a euphoric high, lifting the consumer'smood and therapeutically relieving stress. Indica strains relax muscleand work as general analgesics, also helping with sleep. A cancerpatient hoping to relieve the pain from chemotherapy would benefitgreatly from the effects of an Indica plant bud, whereas an individualdealing with depression would better benefit from an extract from Sativaplant. Sativa's has low or no CBD levels. Indica's chemical profileshows a more balanced mix, with moderate THC levels and higher levels ofCBD. Differences in the chemical composition of Cannabis varieties mayproduce different effects in humans. Synthetic THC, called dronabinol(Marinol), does not contain CBD, CBN, or other cannabinoids, which isone reason why its pharmacological effects may differ significantly fromthose of natural Cannabis. Hybridization and crosses of all three existsand are of particular interest, especially if breeding for certaincannabinoid percentage profiles. (i.e., High THC/High CBD, Low THC/HighCBD).

2.2.3 Cannabidiol

Cannabidiol (CBD) is not psychoactive, and was thought not to affect thepsychoactivity of THC. However, recent evidence shows that smokers ofcannabis with a higher CBD/THC ratio were less likely to experienceschizophrenia-like symptoms. Cannabidiol has little affinity for CB1 andCB2 receptors but acts as an indirect antagonist of cannabinoidagonists. It is an antagonist at the putative new cannabinoid receptor,GPR55, a GPCR expressed in the caudate nucleus and putamen. Cannabidiolhas also been shown to act as a 5-HT1A receptor agonist, an action thatis involved in its antidepressant, anxiolytic, and neuroprotectiveeffects. It appears to relieve convulsion, inflammation, anxiety, andnausea. CBD has a greater affinity for the CB2 receptor than for the CB1receptor. CBD shares a precursor with THC and is the main cannabinoid inlow-THC Cannabis strains. CBD apparently plays a role in preventing theshort-term memory loss associated with THC in mammals.

2.2.4 Cannabinol

Cannabinol (CBN) is the primary product of THC degradation, and there isusually little of it in a fresh plant. CBN content increases as THCdegrades in storage, and with exposure to light and air. It is onlymildly psychoactive. Its affinity to the CB2 receptor is higher than forthe CB1 receptor.

2.2.5 Cannabigerol

Cannabigerol (CBG) is non-psychotomimetic but still affects the overalleffects of Cannabis. It acts as an α2-adrenergic receptor agonist,5-HT1A receptor antagonist, and CB1 receptor antagonist. It also bindsto the CB2 receptor.

2.2.6 Tetrahydrocannabivarin

Tetrahydrocannabivarin (THCV) is prevalent in certain central Asian andsouthern African strains of Cannabis. It is an antagonist of THC at CB1receptors and attenuates the psychoactive effects of THC.

2.2.7 Cannabidivarin

Although cannabidivarin (CBDV) is usually a minor constituent of thecannabinoid profile, enhanced levels of CBDV have been reported in feralcannabis plants from the northwest Himalayas, and in hashish from Nepal.

2.2.8 Cannabichromene

Cannabichromene (CBC) is non-psychoactive and does not affect thepsychoactivity of THC. Cannabichromene is more common in tropicalcannabis varieties. Effects include anti-inflammatory and analgesic. THCIt is found in nearly all tissues in a wide range of animals. Twoanalogs ofanandamide, 7,10,13,16-docosatetraenoylethanolamide and“homo”-y-linolenoylethanolamine, have similar pharmacology. All of theseare members of a family of signaling lipids called“N”-acylethanolamides, which also includes the noncannabimimeticpalmitoylethanolamide and oleoylethanolamine, which possessanti-inflammatory and orexigenic effects, respectively. Many“N”-acylethanolamines have also been identified in plant seeds and inmolluscs.

2.2.9 Cannabicyclol

Cannabicyclol (CBL) is a non-psychoactive cannabinoid found in thecannabis species. CBL is a degradative product like Cannabinol. Lightconverts Cannabichromene to CBL and it contains 16 stereoisomer.

2.2.10 Cannabivarin Cannabivarin (CBV) is a non-psychoactive cannabinoidfound in minor amounts in cannabis plant. It is an analog of cannabinol(CBN). Cannabivarin is an oxidation product of Tetrahydrocannabivarin(THCV)

2.3 Other Phytocannabinoids

The compositions of the present invention may also utilizephytocannabinoids from several other several plant species besidescannabis. These include Echinacea purpurea, Echinacea angustifolia,Echinacea pallida, Acmella oleracea, Helichrysum umbraculigerum, andRadula marginata. The best known cannabinoids that are not derived fromCannabis are the lipophilic alkamides (alkylamides) from Echinaceaspecies. At least 25 different alkylamides(dodeca-2E,4E,8Z,10E/Z-tetraenoic-acid-isobutylamides) have beenidentified, and some of them have shown affinities to the CB2-receptor.In Echinacea species, cannabinoids are found throughout the plantstructure, but are most concentrated in the roots and flowers. Yangoninfound in the Kava plant is a ligand on the CB1 receptor. Tea (Camelliasinensis) catechins have an affinity for human cannabinoid receptors. Awide spread dietary cannabinoid, beta-caryophyllene, a component fromthe essential oil of cannabis and other medicinal plants, has also beenidentified as a selective agonist of peripheral CB2-receptors, in vivo.

2.4 Synthetic Cannabinoids

In addition to the natural cannabinoids described above for use in thesecond composition of the present invention, synthetic cannabinoids mayalso be used. One of ordinary skill in the art can readily synthesizenumerous synthetic cannabinoids for use in the compositions and methodsof the present invention. Non-limiting representative examples of suchsynthetic cannabinoids include, for example, Dronabinol (Marinol)(Δ9-tetrahydrocannabinol (THC)), used as an appetite stimulant,anti-emetic, and analgesic; Nabilone (Cesamet), a synthetic cannabinoidand an analog of Marinol; Sativex, a cannabinoid extract oral spraycontaining THC, CBD, and other cannabinoids used for neuropathic painand spasticity in 22 countries including England, Canada and Spain; andRimonabant (SR141716), a selective cannabinoid (CB1) receptor inverseagonist once used as an anti-obesity drug under the proprietary nameAcomplia.

2.5 Endocannabinoids

The endogenous cannabinoid system (ECS) is perhaps the most importantphysiological system involved in establishing and maintaining humanhealth through homeostasis. Found throughout the body the ECSendocannabinoids serve as intercellular lipid messengers. Although inthis intracellular signaling role they are similar to the well-knownmonoamine neurotransmitters, such as acetylcholine and dopamine,endocannabinoids differ in numerous ways from them. For instance, theyuse retrograde signaling. Non limiting examples of endocannabinoids thatmay be modulated by the compositions and methods of the presentinvention include, for example, those endocannabinoids listed below.

2.5.1 N-arachidonoylethanolamine

N-arachidonoylethanolamine (AEA), also known as Anandamide, is anendogenous cannabinoid neurotransmitter. It is synthesized fromN-arachidonoyl phosphatidylethanolamine by multiple pathways. It isdegraded primarily by the fatty acid amide hydrolase (FAAH) enzyme,which converts anandamide into ethanolamine and arachidonic acid.Inhibitors of FAAH lead to elevated anandamide levels and are beingpursued for therapeutic use and treatments. Anandamide's effects can beeither central, in the brain, or peripheral, in other parts of the body.These effects are mediated by the CB1 receptors in the CNS, and the CB2receptors in the periphery, which is involved in homeostasis andfunctions of the immune system.

2.5.2 2-arachidonoyl glycerol (2-AG)

Another endocannabinoid, 2-arachidonoyl glycerol, binds to both the CB1and CB2 receptors with similar affinity, acting as a full agonist atboth, and there is some controversy over whether 2-AG rather thananandamide is chiefly responsible for endocannabinoid signaling in vivo.In particular, one in vitro study suggests that 2-AG is capable ofstimulating higher G-protein activation than anandamide, although thephysiological implications of this finding are not yet known.

2.5.3 2-Arachidonyl Glyceryl Ether (Noladin Ether)

Endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isisolated from porcine brain. Previously, it had been synthesized as astable analog of 2-AG; indeed, some controversy remains over itsclassification as an endocannabinoid, as another group failed to detectthe substance at “any appreciable amount” in the brains of severaldifferent mammalian species. Noladin ether binds to the CB1 cannabinoidreceptor (“K”i=21.2 nmol/L) and causes sedation, hypothermia, intestinalimmobility, and mild antinociception in mice. It binds primarily to theCB1 receptor, and only weakly to the CB2 receptor. Like anandamide, NADAis also an agonist for the vanilloid receptor subtype 1 (TRPV1), amember of the vanilloid receptor family.

2.5.4 Virodhamine (OAE)

Virodhamine, or “0”-arachidonoyl-ethanolamine (OAE), is a full agonistat CB2 and a partial agonist at CB1, although it behaves as a CB1antagonist “in vivo”. In rats, Virodhamine was found to be present atcomparable or slightly lower concentrations than anandamide in thebrain, but 2- to 9-fold higher concentrations peripherally.

2.5.5 Function of Endocannabinoids

Endocannabinoids serve as intercellular ‘lipid messengers’, signalingmolecules that are released from one cell and activate the cannabinoidreceptors present on other nearby cells. Although in this intercellularsignaling role they are similar to the well-known monoamineneurotransmitters, such as acetylcholine and dopamine, endocannabinoidsdiffer in numerous ways from them. For instance, they use retrogradesignaling. Furthermore, endocannabinoids are lipophilic molecules thatare not very soluble in water. They are not stored in vesicles, andexist as integral constituents of the membrane bilayers that make upcells. They are believed to be synthesized ‘on-demand’ rather than madeand stored for later use. The mechanisms and enzymes underlying thebiosynthesis of endocannabinoids remain elusive and continue to be anarea of active research. The endocannabinoid 2-AG has been found inbovine and human maternal milk.

2.5.6 Retrograde Signal

Conventional neurotransmitters are released from a ‘presynaptic’ celland activate appropriate receptors on a ‘postsynaptic’ cell, wherepresynaptic and postsynaptic designate the sending and receiving sidesof a synapse, respectively. Endocannabinoids, on the other hand, aredescribed as retrograde transmitters because they most commonly travel‘backwards’ against the usual synaptic transmitter flow. They are, ineffect, released from the postsynaptic cell and act on the presynapticcell, where the target receptors are densely concentrated on axonalterminals in the zones from which conventional neurotransmitters arereleased. Activation of cannabinoid receptors temporarily reduces theamount of conventional neurotransmitter released. This endocannabinoidmediated system permits the postsynaptic cell to control its ownincoming synaptic traffic. The ultimate effect on theendocannabinoid-releasing cell depends on the nature of the conventionaltransmitter being controlled. For instance, when the release of theinhibitory transmitter GABA is reduced, the net effect is an increase inthe excitability of the endocannabinoid-releasing cell.

3. Compositions and Therapeutic Methods

The novel combination of a balanced PC composition with one or morecannabinoids, which are synergistic when used in combination, results ineasy delivery of and passage of a balanced PC composition andcannabinoids through the cell membrane and the blood brain barrier tosupport tissue regeneration, to inhibit the inflammatory reactions andto promote cerebral reperfusion.

Thus, in one embodiment, this invention is directed to a firstcomposition for use with a second composition for ameliorating ortreating one or more symptoms of seizures, Alzheimer's, depression, andatherosclerosis in a subject, wherein said first composition comprises(a) a therapeutically effective amount of a first composition comprisinga balanced PC composition; and (b) a therapeutically effective amount ofa second composition comprising one or more cannabinoids, a natural orsynthetic derivative thereof, or a salt thereof, wherein said firstcomposition and said second composition are each optionally andindependently administered together with a pharmaceutically acceptablecarrier or diluent.

In one embodiment, treatment of symptoms of seizure is manifested by aslowing of the progression of one or more of the aforementioned symptomsor effects of seizures listed supra.

In another embodiment, this invention is directed to a first compositionfor use with a second composition for achieving an anti-epileptic effectin a subject suffering from epilepsy, refractory, partial-complexepilepsy, temporal lobe epilepsy, or a combination thereof, wherein saidfirst composition comprises (a) a therapeutically effective amount of afirst composition comprising a balanced PC composition; and (b) atherapeutically effective amount of a second composition comprising oneor more cannabinoids, a natural or synthetic derivative thereof, or asalt thereof, wherein said first composition and said second compositionare each optionally and independently administered together with apharmaceutically acceptable carrier or diluent.

In certain embodiments, the anti-epileptic effect is manifested by aslowing of the progression of one or more symptoms or effects ofepilepsy including, for example, and not by way of limitation, staringspells, loss of alertness, violent shaking, strange sensation such astingling, smelling an odor that is not present, or emotional changesprior to each seizure (aura), depression, cognitive decline, death, orany combination thereof.

In yet another embodiment, this invention is directed to a firstcomposition for use with a second composition for achieving ananti-“Grand Mal” or generalized tonic-clonic effect in a subjectsuffering from Grand Mal” or generalized tonic-clonic, wherein saidfirst composition comprises (a) a therapeutically effective amount of afirst composition comprising a balanced PC composition; and (b) atherapeutically effective amount of a second composition comprising oneor more cannabinoids, a natural or synthetic derivative thereof, or asalt thereof, wherein said first composition and said second compositionare each optionally and independently administered together with apharmaceutically acceptable carrier or diluent.

In certain embodiments, the anti-“Grand Mal” or generalized tonic-cloniceffect is manifested by a slowing of the progression of one or moresymptoms or effects of seizure including, for example, and not by way oflimitation, muscle stiffness and rigidity (the “tonic” phase),unconsciousness, convulsions, muscle rigidity, repetitive, jerkingmovements, repetitive, rhythmic jerks on both sides of the body, violentjerking (the “clonic” phase), injuries and accidents tongue biting,urinary incontinence, deep sleep (the “postictal” or after-seizurephase), or any combination thereof.

In yet another embodiment, this invention is also directed to a firstcomposition for use with a second composition for achieving ananti-absence seizure effect in a subject suffering from absence seizure,wherein said first composition comprises (a) a therapeutically effectiveamount of a first composition comprising a balanced PC composition; and(b) a therapeutically effective amount of a second compositioncomprising one or more cannabinoids, a natural or synthetic derivativethereof, or a salt thereof, wherein said first composition and saidsecond composition are each optionally and independently administeredtogether with a pharmaceutically acceptable carrier or diluent.

In certain embodiments, said anti-absence seizure effect is manifestedby a slowing of the progression of one or more symptoms or effects ofabsence seizure including, for example, and not by way of limitation,short loss of consciousness (just a few seconds) with few or nosymptoms, interruption of daily activity, blank stares, “losing time”,or any combination thereof.

In yet another embodiment, this invention is also directed to a firstcomposition for use with a second composition for achieving ananti-myoclonic sporadic seizures (isolated) effect in a subject at riskof suffering from myoclonic sporadic seizures, wherein said firstcomposition comprises (a) a therapeutically effective amount of a firstcomposition comprising a balanced PC composition; and (b) atherapeutically effective amount of a second composition comprising oneor more cannabinoids, a natural or synthetic derivative thereof, or asalt thereof, wherein said first composition and said second compositionare each optionally and independently administered together with apharmaceutically acceptable carrier or diluent.

In certain embodiments, said anti-myoclonic sporadic seizure effect ismanifested by a slowing of the progression of one or more symptoms oreffects of myoclonic sporadic seizures including, for example, and notby way of limitation, jerking movements usually on both sides of thebody, dropping or involuntarily throwing objects, or any combinationthereof.

In yet another embodiment, this invention is also directed to a firstcomposition for use with a second composition for achieving ananti-atonic seizures effect in a subject at risk of suffering fromatonic seizures, wherein said first composition comprises (a) atherapeutically effective amount of a first composition comprising abalanced PC composition; and (b) a therapeutically effective amount of asecond composition comprising one or more cannabinoids, a natural orsynthetic derivative thereof, or a salt thereof, wherein said firstcomposition and said second composition are each optionally andindependently administered together with a pharmaceutically acceptablecarrier or diluent.

In certain embodiments, said anti-atonic seizure effect is manifested bya slowing of the progression of one or more symptoms or effects ofatonic seizures including, for example, and not by way of limitation, asudden and general loss of muscle tone, particularly in the arms andlegs, falling, or any combination thereof.

In yet another embodiment, this invention is also directed to a firstcomposition for use with a second composition for achieving ananti-simple partial seizures comprising focus, simple (awarenessretained), simple motor, simple sensory, and simple psychologicalseizures effect in a subject suffering from the one or more of theaforementioned seizures, wherein said first composition comprises (a) atherapeutically effective amount of a first composition comprising abalanced PC composition; and (b) a therapeutically effective amount of asecond composition comprising one or more cannabinoids, a natural orsynthetic derivative thereof, or a salt thereof, wherein said firstcomposition and said second composition are each optionally andindependently administered together with a pharmaceutically acceptablecarrier or diluent.

In certain embodiments, said anti-simple partial seizure effect ismanifested by a slowing of the progression of one or more symptoms oreffects of simple partial seizure including, for example, and not by wayof limitation, motor symptoms such as jerking, muscle rigidity, spasms,head-turning, sensory such as unusual sensations affecting either thevision, hearing, smell taste or touch, and psychological such as memoryor emotional disturbances, or any combination thereof.

In yet another embodiment, this invention is also directed to a firstcomposition for use with a second composition for achieving ananti-complex partial seizure (impairment of awareness) effect in asubject suffering from complex partial seizure, wherein said firstcomposition comprises (a) a therapeutically effective amount of a firstcomposition comprising a balanced PC composition; and (b) atherapeutically effective amount of a second composition comprising oneor more cannabinoids, a natural or synthetic derivative thereof, or asalt thereof, wherein said first composition and said second compositionare each optionally and independently administered together with apharmaceutically acceptable carrier or diluent.

In certain embodiments, said anti-complex partial seizure effect ismanifested by a slowing of the progression of one or more symptoms oreffects of complex partial seizure including, for example, and not byway of limitation, automatisms such as lip smacking, chewing, fidgeting,walking and other repetitive, involuntary but coordinated movements, orany combination thereof.

In yet another embodiment, this invention is also directed to a firstcomposition for use with a second composition for achieving ananti-nocturnal seizure effect in a subject suffering from nocturnalseizure, wherein said first composition comprises (a) a therapeuticallyeffective amount of a first composition comprising a balanced PCcomposition; and (b) a therapeutically effective amount of a secondcomposition comprising one or more cannabinoids, a natural or syntheticderivative thereof, or a salt thereof, wherein said first compositionand said second composition are each optionally and independentlyadministered together with a pharmaceutically acceptable carrier ordiluent.

In certain embodiments, said anti-nocturnal seizure effect is manifestedby a slowing of the progression of one or more symptoms or effects ofnocturnal seizure including, for example, and not by way of limitation,unusual differences upon awakening, headache, bed wetting, tonguebiting, bone or joint injury, light-headedness, unusual mentalbehaviors, or any combination thereof.

In yet another embodiment, this invention is also directed to a methodfor treating a mammal which has been diagnosed as suffering fromepilepsy, refractory, partial-complex epilepsy, temporal lobe epilepsy,seizure, Grand Mal or generalized tonic-clonic seizure, absence seizure,myoclonic sporadic seizures, atonic seizures, simple partial seizurescomprising focus, simple (awareness is retained), simple motor, simplesensory, and simple psychological seizures, complex partial seizure,nocturnal seizure, or an combination thereof, and who is in need oftherapeutic treatment comprising administering to said subject (a) atherapeutically effective amount of a first composition comprising abalanced PC composition; and (b) a therapeutically effective amount of asecond composition comprising one or more cannabinoids, a natural orsynthetic derivative thereof, or a salt thereof; wherein said firstcomposition and said second composition are each optionally andindependently administered together with a pharmaceutically acceptablecarrier or diluent, and wherein said therapeutic treatment isprevention, treatment or amelioration of one or more of theaforementioned symptoms listed supra of epilepsy, seizure, Grand Mal orgeneralized tonic-clonic seizure, absence seizure, myoclonic sporadicseizures, atonic seizures, simple partial seizures comprising focus,simple (awareness retained), simple motor, simple sensory, and simplepsychological seizures, complex partial seizures, nocturnal seizures, orany combination thereof.

Cannabinoids are medically efficacious for a variety of ailments anddiseases. Specifically, cannabinoids are inhibitory to plaque formation,anti-oxidative in nature, impair the formation of cholesteryl esters,and act as vasodilators and smooth muscle relaxants in arterial walls;all of which are beneficial in treating symptoms of seizures and relateddiseases or disorders.

One of the main variables of membrane lipid composition is thequantitative relationships between sphingomyelin, phosphatidylcholine,and cholesterol, which are the main lipid components of the outermonolayer of mammalian plasma membranes. In most normal cells, there isa gradient of sphingomyelin from the cell boundary to cell center; itshighest content is in the plasma membrane, the lowest in the innermitochondrial membrane and the nuclear membrane. In the mammalian plasmamembrane, the two choline-containing lipids, phosphatidylcholine andsphingomyelin, constitute more than 50% of the total phospholipid.Sphingomyelin content increases with aging, especially in tissues whichhave a relatively low phospholipid turnover. It also increases inseveral diseases, including atherosclerosis and certain types of cancer.For example, a 6-fold change in the sphingomyelin to phosphatidylcholinemole ratio takes place in the aorta and arterial wall during aging ofnormal humans. The change of this ratio in atherosclerosis is even morestriking. In this disease, the sphingomyelin content can be as high as70-80% of the total phospholipids in advanced aortic lesions.

In general, there is a strong positive correlation between the contentof sphingomyelin and cholesterol in membranes. In addition, changes inthe content of one are followed by comparable changes in the other.Indeed, it is still not clear how cells maintain the various lipidcompositions in their different membranes despite the transfer andexchange of lipids among membranes in vivo. Pathological changes insphingomyelin content might result from changes in the metabolism of thecompound, i.e. increase in its rate of biosynthesis, reduction in itsrate of degradation, or change in relative rate in phospholipid transferin or out of cells. The change taking place in one membrane might remainlocalized or it may be propagated to other membranes of the cell bytransfer of lipid. The relative content of phosphatidylcholine,sphingomyelin, and cholesterol appears to vary in different membranesystems and even within the same membrane under different conditions.

It is believed that oxidized lipids contribute to heart disease both byincreasing deposition of calcium on the arterial wall, a major hallmarkof atherosclerosis, and by interrupting blood flow, a major contributorto heart attack and sudden death. Oxidized cholesterol (oxysterols)enhances the production of sphingomyelin, which is the elevatedphospholipid found in the cellular membranes of occluded coronaryarteries. The increase of sphingomyelin content in the cell membraneenhances the interaction between the membrane and ionic calcium (Ca²⁺),thereby increasing the risk of arterial calcification Without intendingto be limited to a specific mechanism of action, one possible mechanismof action of the combination therapy of the present invention is througha cascade of one or more biochemical pathways that result invasodilation and blood thinning, which in turn results in thesignificant reduction of blood lipids triglyceride, LDL and cholesterol.As a result of the administration of a balanced PC composition that hasa blood thinning effect according to the present invention, thetransport of one or more cannabinoids through cell membranes and theblood brain barrier is further facilitated. Because of the ease andefficiency of transport of cannabinoids that is caused by use of abalanced PC composition, the effective concentration of cannabinoids canbe reduced by as much as about 10 fold to about 100 fold or more withoutreducing the therapeutic effectiveness of this drug.

The optimization of dosing of cannabinoids achieved with thecompositions and methods of the present invention has tremendousclinical advantages in preventing the one or more side effects of use ofcannabinoids including, for example, and not by away of limitation,those effects such as dysphoria, anxiety or panic, impairment of memory,reductions in psychomotor and cognitive performance, disorderedperception of the passage of time, and euphoria, schizophrenicpsychosis, tiredness, dizziness, tachycardia, orthostatic hypotension,dry mouth, reduced lacrimation, muscle relaxation, and increasedappetite, potential irreversible cognitive impairments (albeit when usedat high concentrations or when being used in children adolescents(particularly before puberty)) or any combination thereof that are knownside effects of any cannabinoid-based therapy

Thus, without intending to be limited to any specific mechanism ofaction, it is believed that subjects exhibiting symptoms or deleteriouseffects of seizures or related diseases or disorders or those subjectssusceptible to those diseases or disorders have a heightenedsphingomyelin to phosphatidylcholine relative ratio. Furthermore, thecombination therapy of the invention results in a decrease in therelative sphingomyelin to phosphatidylcholine mass ratio. A non-limitingexample of the beneficial sphingomyelin to phosphatidylcholine massratio achieved with the compositions and methods of the presentinvention is approximately 1.2-4.2. It is this decrease in thesphingomyelin to phosphatidylcholine ratio that serves to reduce orameliorate the symptoms of seizures or related diseases or disorders.

The cannabinoids for use in the compositions and methods of the presentinvention are isolated endogenous cannabinoids, phytocannabinoids,recombinant cannabinoids, or a combination thereof, or can beadministered exogenously, or may be administered through a combinationof both endogenous and exogenous sources of cannabinoids. In general,administration of cannabinoids with a balanced PC composition increasesthe bioavailability of cannabinoids.

The compositions and methods of the present invention are beneficial invariety of bodily functions, including, by way of example and notlimitation, reduction of calcification and plaque, the lowering badcholesterol (LDL), reducing oxidative damages, and acting as avasodilator and relaxant of smooth muscle cells, which would result inincreasing blood flow and decreasing blood pressure.

4. Formulation and Modes of Administration

The terms “treat”, “treated”, “treating” and “treatment” are to bebroadly understood as referring to any response to, or anticipation of,a medical condition in a mammal, particularly a human, and includes butis not limited to: (i) preventing the medical condition from occurringin a subject, which may or may not be predisposed to the condition, buthas not yet been diagnosed with the condition and, accordingly, thetreatment constitutes prophylactic treatment for the medical condition;(ii) inhibiting the medical condition, i.e., arresting, slowing ordelaying the onset, development or progression of the medical condition;or (iii) relieving the medical condition, i.e., causing regression ofthe medical condition.

The term “therapeutically effective amount” or “therapeutically and/orprophylactically effective amount” as used herein refers to an amount ofcompound or agent that is sufficient to elicit the required or desiredtherapeutic and/or prophylactic response, as the particular treatmentcontext may require.

It will be understood that a therapeutically and/or prophylacticallyeffective amount of a drug for a subject is dependent inter alia on thebody weight of the subject as well as other factors known to a person ofordinary skill in the art. A “subject” herein to which a therapeuticagent or composition thereof can be administered includes mammals suchas a human subject of either sex and of any age, and also includes anynonhuman animal, particularly a domestic or companion animal,illustratively a cat, dog or a horse as well as laboratory animals suchas guinea pigs.

As used herein, an “effective amount” of a composition is an amountsufficient to achieve a desired biological effect, in this case at leastone of modulation of activity and/or development of cell populationsand/or tissues that are targeted by the combination therapy of theinvention. It is understood that the effective dosage will be dependentupon the age, sex, health, and weight of the recipient, kind ofconcurrent treatment, if any, frequency of treatment, and the nature ofthe effect desired. The most preferred dosage will be tailored to theindividual subject, as is understood and determinable by one of skill inthe art, without undue experimentation.

As used herein, a “subject” is any mammal, in particular a primate,preferably a human, that 1) exhibits at least one symptom associatedwith impairment of tissue development and activity, or 2) and has beendiagnosed with or is at the risk of developing a disease or disorderthat is causes in impairment of tissue development and activity.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopcia or other generally recognizedpharmacopcia for use in animals, and more particularly in humans.

The term “carrier” refers to a diluent, adjuvant, excipient, or vehiclewith which the therapeutic is administered. In one embodiment, thetherapeutically effective amount of the balanced PC composition of thepresent invention itself serves as the pharmaceutical carrier for theone or more cannabinoids (for example, and not by way of limitation, thebalanced PC composition serves as a liposome, a micelle, or a smallunilamellar vesicle (SUV) for the entrapment of the therapeuticallyeffective amount of one or more cannabinoids. Such pharmaceuticalcarriers can be sterile liquids, such as water and oils, including thoseof petroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. Preferred oil isessential fatty acids, linoleic acid and linolenic acid. Water is apreferred carrier when the pharmaceutical composition is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid carriers, particularly forinjectable solutions.

The terms “BodyBio balanced PC” and “balanced PC” are usedinterchangeably herein.

The active compositions of the invention having tissue modulatoryactivities as described herein are provided as isolated andsubstantially purified compounds in pharmaceutically acceptableformulations using formulation methods known to those of ordinary skillin the art. These formulations can be administered by standard routes.

Suitable pharmaceutical excipients include starch, glucose, lactose,sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. The composition, ifdesired, can also contain minor amounts of wetting or emulsifyingagents, or pH buffering agents. These compositions can take the form ofsolutions, suspensions, emulsion, tablets, pills, capsules, powders,sustained-release formulations and the like. The composition can beformulated as a suppository, with traditional binders and carriers suchas triglycerides.

The compositions of the invention can be formulated as neutral or saltforms. Pharmaceutically acceptable salts include those formed withanions such as those derived from hydrochloric, phosphoric, acetic,oxalic, tartaric acids, etc., and those formed with cations such asthose derived from sodium, potassium, ammonium, calcium, ferrichydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol,histidine, procaine, etc.

In general, the combinations may be administered by the transdermal,intraperitoneal, intracranial, intracerebroventricular, intracerebral,intravaginal, intrauterine, oral, rectal, ophthalmic (includingintravitreal or intracameral), nasal, topical (including buccal andsublingual), parenteral (including subcutaneous, intraperitoneal,intramuscular, intravenous, intradermal, intracranial, intratracheal,and epidural and nasal) administration. Parenteral administrationincludes direct or indirect injection into cells, tissues or organs invivo, ex vivo or in vitro.

In one embodiment, the combination therapy comprising use of a firstcomposition comprising a balanced PC composition and the secondcomposition comprising one or more cannabinoids is administered throughone or more different or the same routes of administration in a singleor multiple regimen. In one embodiment, first composition comprising abalanced PC composition and the second composition comprising one ormore cannabinoids can be administered by a variety of routes and modesof administration, including for example, and not by way of limitation,intravenous routes, transdermal routes, intranasal routes, parenteralroutes, oral routes or a combination thereof. In one embodiment, thefirst composition comprising a balanced PC composition and the secondcomposition comprising one or more cannabinoids is administered once,twice, three, four or more times daily through, IV routes, oral routes,or a combination of both.

Oral formulation can include standard carriers such as pharmaceuticalgrades of mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, cellulose, magnesium carbonate, etc. Examples of suitablepharmaceutical carriers are described in “Remington's PharmaceuticalSciences” by E. W. Martin. Such compositions will contain atherapeutically effective amount of the compound, preferably in purifiedform, together with a suitable amount of carrier so as to provide theform for proper administration to the patient. The formulation shouldsuit the mode of administration.

In one embodiment, the composition is formulated in accordance withroutine procedures as a pharmaceutical composition adapted forintravenous administration to human beings. Typically, compositions forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the composition may also include a solubilizingagent and a local anesthetic such as lignocaine to ease pain at the siteof the injection. Generally, the ingredients are supplied eitherseparately or mixed together in unit dosage form, for example, as a drylyophilized powder or water free concentrate in a hermetically sealedcontainer such as an ampoule or sachets indicating the quantity ofactive agent. Where the composition is to be administered by infusion,it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided. The compositions are administered separately orare mixed together prior to administration.

In one embodiment, the first composition, the second composition or bothmay be incorporated into biodegradable polymers allowing for sustainedrelease of the compound, the polymers being implanted in the vicinity ofwhere drug delivery is desired or implanted so that the composition isslowly released systemically. Osmotic mini-pumps may also be used toprovide controlled delivery of the first composition, the secondcomposition or both through cannulae to the site of interest, such asdirectly into the site of injury. The biodegradable polymers and theiruse are described, for example, in detail in Brem et al., J. Neurosurg.74: 441-446 (1991), which is hereby incorporated by reference in itsentirety.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampoules and vials, and may be stored ina freeze-dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example, water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

The composition formulations may conveniently be presented in unitdosage form and may be prepared by conventional pharmaceuticaltechniques. Such techniques include the step of bringing intoassociation the active ingredient and the pharmaceutical carrier(s) orexcipient(s). In general, the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product.

In another embodiment, the composition of the invention comprises atherapeutically effective amount of a first composition comprising abalanced PC composition formulations and the second compositioncomprising one or more cannabinoids, in a suitable carrier.

A typical regimen for treatment of symptoms of diseases and disordersrelated to impaired development and activities of cells and tissuescomprises administration of an effective amount of the composition asdescribed above, administered as a single treatment, or repeated asenhancing or booster dosages, over a period up to and including one weekto about 48 months or more.

Within other embodiments, the compositions may also be placed in anylocation such that the compounds or constituents are continuouslyreleased. The amount of the composition of the invention which will beeffective in the treatment of symptoms of diseases and disorders relatedto impaired tissue development can be determined by standard clinicaltechniques. In addition, in vitro assays may optionally be employed tohelp identify optimal dosage ranges. In particular, the dosage of thecompositions of the present invention will depend on the disease stateof subject under treatment and other clinical factors such as weight andcondition of the human or animal and the route of administration of thecompounds or compositions. The precise dose to be employed in theformulation, therefore, should be decided according to the judgment ofthe health care practitioner and each patient's circumstances. Effectivedoses may be extrapolated from dose-response curves derived from invitro or animal model test systems.

Various delivery systems are available and can be used to administer thecompositions of the invention, i.e., encapsulation in liposomes,microparticles, microcapsules, recombinant cells capable of expressingthe compound, receptor-mediated endocytosis. Methods of introductioninclude but are not limited to intradermal, intramuscular,intraperitoneal, intravenous, subcutaneous, intranasal, epidural, andoral routes. The compounds or compositions may be administered by anyconvenient route, for example by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (i.e., oralmucosa, rectal and intestinal mucosa, etc.) and may be administeredtogether with other biologically active agents. Administration can besystemic or local.

In addition, it may be desirable to introduce the compounds orcompositions of the invention into the central nervous system by anysuitable route, including intraventricular and intrathecal injection;intraventricular injection may be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir. Pulmonary administration can also be employed, i.e., by useof an inhaler or nebulizer, and formulation with an aerosolizing agent.

In a specific embodiment, it may be desirable to administer thecompositions of the invention locally to the area in need of treatment;this may be achieved by, for example, and not by way of limitation,local infusion during surgery, topical application, i.e., in conjunctionwith a wound dressing after surgery, by injection, by means of acatheter, by means of a suppository, or by means of an implant, theimplant being of a porous, non-porous, or gelatinous material, includingmembranes, such as sialastic membranes, or fibers. Preferably, whenadministering a protein such as cannabis, care must be taken to usematerials to which the protein does not absorb or otherwise interact.

In one embodiment, the compound or composition can be delivered in acontrolled release system. In one embodiment, a pump may be used. Inanother embodiment, polymeric materials can be used. In yet anotherembodiment, a controlled release system can be placed in proximity ofthe therapeutic target, i.e., the brain, thus requiring only a fractionof the systemic dose. Other controlled release systems are discussed inthe review by Langer, Science 249:1527-1533 (1990).

Non-limiting representative examples of various dosage ranges for thefirst composition comprising a balanced PC composition and the secondcomposition comprising one or more cannabinoids are as follows. In oneembodiment, the first composition and/or the second composition isadministered at a dosage of about 50 units/kg, 100 units/kg or 150units/kg at a weekly or biweekly interval. In one embodiment,compositions disclosed herein comprise balanced PC and/or one or morecannabinoids in a total amount of between about 0.1% and about 95% byweight of the combination therapy composition, for example about 0.1%,about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%,about 0.8%, about 0.9%, about 1.0%, about 2%, about 3%, about 4%, about5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, about 90%, or about 95%, or any numerical integer values therebetween.

The compositions of the invention can be in a form suitable for oraluse, according to any technique suitable for the manufacture of oralpharmaceutical compositions as are within the skill in the art. Forexample, the phosphatidylcholine composition and the EFA composition canbe formulated (either separately or together) into soft capsules, oilysuspensions, or emulsions, optionally in admixture with pharmaceuticallyacceptable excipients.

The compositions of the invention are formulated into liquid,semi-liquid, suspension, or solid compositions, such as aqueoussolutions, aqueous or oily suspensions, syrups or elixirs, emulsions,tablets, dispersible powders or granules, hard or soft capsules,optionally in admixture with pharmaceutically acceptable excipients.

5. Adjuvants, Carriers, and Diluents

As would be understood by one of ordinary skill in the art, when acomposition of the present invention is provided to an individual, itcan further comprise at least one of salts, buffers, adjuvants, or othersubstances which are desirable for improving the efficacy of thecomposition. Adjuvants are substances that can be used to specificallyaugment at least one immune response. Normally, the adjuvant and thecomposition are mixed prior to presentation to the immune system, orpresented separately.

The term “carrier” refers to a diluent, adjuvant, excipient, or vehiclewith which the therapeutic is administered. Such pharmaceutical carrierscan be sterile liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. Water is a preferredcarrier when the pharmaceutical composition is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid carriers, particularly forinjectable solutions.

Oral formulation can include standard carriers such as pharmaceuticalgrades of mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, cellulose, magnesium carbonate, etc. Examples of suitablepharmaceutical carriers are described in “Remington's PharmaceuticalSciences” by E. W. Martin. Such compositions will contain atherapeutically effective amount of the compound, preferably in purifiedform, together with a suitable amount of carrier so as to provide theform for proper administration to the patient. The formulation shouldsuit the mode of administration.

Adjuvants can be generally divided into several groups based upon theircomposition. These groups include lipid micelles, oil adjuvants, mineralsalts (for example, AlK(SO₄)₂, AlNa (SO₄)₂, AlNH₄ (SO₄)), silica,kaolin, and certain natural substances, for example, wax D fromMycobacterium tuberculosis, substances found in Corynebacterium parvum,or Bordetella pertussis, Freund's adjuvant (DIFCO), alum adjuvant(Alhydrogel), MF-50 (Chiron) Novasomes™, or micelles, among others.

Suitable excipients for liquid formulation include water or saline,suspending agents such as sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing orwetting agents such as lecithin, condensation products of an alkyleneoxide with fatty acids (e.g., polyoxethylene stearate), condensationproducts of ethylene oxide with long chain aliphatic alcohols (e.g.,heptadecethyleneoxy-cetanol), condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol (e.g.,polyoxyethylene sorbitol monooleate), or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides (e.g., polyoxyethylene sorbitan monooleate).

Suitable excipients for solid formulations include calcium carbonate,sodium carbonate, lactose, calcium phosphate, or sodium phosphate;granulating and disintegrating agents such as maize starch, or alginicacid; binding agents such as starch, gelatin, or acacia; and lubricatingagents such as magnesium stearate, stearic acids, or talc, and inertsolid diluents such as calcium carbonate, calcium phosphate, or kaolin.

Other suitable excipients include starch, glucose, lactose, sucrose,gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerolmonostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. The composition, ifdesired, can also contain minor amounts of wetting or emulsifyingagents, or pH buffering agents. These compositions can take the form ofsolutions, suspensions, emulsion, tablets, pills, capsules, powders,sustained-release formulations and the like. The composition can beformulated as a suppository, with traditional binders and carriers suchas triglycerides.

The amount of the composition of the invention which will be effectivein the treatment, inhibition and prevention of a disease or disorderassociated with tissue or cell impairment can be determined by standardclinical techniques. In addition, in vitro assays may optionally beemployed to help identify optimal dosage ranges.

In particular, the dosage of the composition of the present inventionwill depend on the disease state or condition being treated and otherclinical factors such as weight and condition of the human or animal andthe route of administration of the compound. The precise dose to beemployed in the formulation, therefore, should be decided according tothe judgment of the practitioner and each patient's circumstances.Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For treating humans or animals, between approximately 0.5 to 500mg/kilogram, is a typical broad range for administering thepharmaceutical composition of the invention. The methods of the presentinvention contemplate single as well as multiple administrations, giveneither simultaneously or over an extended period of time. It is to beunderstood that the present invention has application for both human andveterinary use.

Preferred unit dosage formulations are those containing a daily dose orunit, daily sub-dose, as herein above recited, or an appropriatefraction thereof, of the administered ingredient. It should beunderstood that in addition to the ingredients, particularly mentionedabove, the formulations of the present invention may include otheragents conventional in the art having regard to the type of formulationin question.

6. Test Kits

The invention also provides a combination therapy pack or kit comprisingone or more containers filled with one or more compositions comprising abalanced PC composition and one or more cannabinoid compositions of thecombined therapy of the invention. The kits are provided for thetreatment of the symptoms of disease and disorders related to impaireddevelopment and activities of cells and tissues and in particularsymptoms of disease related to imbalance of essential fatty acids,including seizure, depression, dementia, Alzheimer disease, andatherosclerosis. In one embodiment, the kit comprises instructions fortreating seizures or a related disease or disorder as described supra ina subject and one or more of the following components: 1) a firstcomposition comprising a balanced PC composition; 2) a secondcomposition comprising one or more cannabinoids; and 3) optionallyassociated with such container(s) can be a notice in the form prescribedby a governmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration.

If a particular component is not included in the kit, the kit canoptionally comprise information on where to obtain the missingcomponent, for example an order form or uniform resource locator for theinternet specifying a website where the component can be obtained. Theinstructions provided with the kit describe the practice of the methodsof the invention as described above, and the route of administration andeffective concentration and the dosing regimen for each of thecompositions provided therein.

This invention is further illustrated by the following examples, whichare not to be construed in any way as imposing limitations upon thescope thereof. On the contrary, it is to be clearly understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which, after reading the description herein, maysuggest themselves to those skilled in the art without departing fromthe spirit of the present invention and/or the scope of the appendedclaims. The contents of all references, patents and published patentapplications cited throughout this application are expresslyincorporated herein by reference.

EXAMPLES Example 1 Production of Bodybio Balanced PC

BodyBio Balanced PC contains phosphatidyl-choline,phosphatidyl-ethanolamine, phosphatidyl-inositol, phosphatidic acid, andmixed glycerol phospholipids formulated as a water-soluble supplementextracted from soy lecithin (lecithin is oil based and is notwater-soluble)(herein referred to as “BodyBio Balanced PC” or “balancedPC”).

The fatty acids and phospholipid concentrations in the intermediatephosphatidylcholine compound are presented below. These percentagevalues provided below represent a non-limiting example of the fatty acidcontent and of the various phospholipids found in the composition.

Fatty Acid Content: C16.0 16.1% C16.1 0.1% C18.0 4.1% C18.1 10.0%

C18.2 55.30% (omega 6)C18.3 14.0% (omega 3)

C22.0 0.4% Phospholipids:

Phosphotidylcholine (PC): about 29%Phosphotidylethanolamine (PE): about 16%Phosphatidyl inositol (PI): about 9%Phosphatidic Acid (PA): about 4%Phosphatidylglycerol (PG): about 1%Total PLs: about 61%

Example 2 Production of Bodybio Balanced PC Cannabinoid CombinationComposition

Prepare BodyBio Balanced PC as in Example 1, Supra.

Prepare a 1:1 mix of Tetrahydrocannabinol (THC) and Cannabidiol (CBD).

Dissolve 1:1 mix of THC and CBD in pure deionized RO water.

Add ⅓ BodyBio balanced PC into the 1:1 mix of THC and CBD dissolved inpure deionized RO water and agitate violently for 5-10 seconds toproduce a gelatinous state.

The BodyBio balanced PC composition—cannabinoid composition was thentreated with a Sonic mixer (e.g., with a Branson 250 Sonic mixer) togenerate a liposome size of approximately 5-10 microns.

In other embodiments, the liposomes are small unilamellar vesicles(SUVs) having sizes predominantly between 0.02 and 0.08 microns in size.

Example 3 Treatment of Patients with Epileptic Seizures with CombinationTherapy Case History: Intractable Epilepsy, Seizures

Patient Background: A 12-year old female presents with an intractable,inherited seizures disorder, Dravet Syndrome, and who is wheelchairbound. Seizure activity typically 3 grand mal seizures primarily whilesleeping in the evening. Height: 4′6″, Weight: 66 lbs.

Presenting symptoms include cognitive challenges, poor coordination,tremors, learning problems memory deficits, unable to walk, insomnia,heart palpitations, hair loss, urinary frequency, and drooling.

-   -   Clinical history: Dravet Syndrome severe myoclonic epilepsy of        infancy, onset Age 5 months    -   Ketogenic Diet (high fat) tried and failed. Break through,        uncontrolled seizure activity with every anti-convulsant        medication attempted.    -   Current Medications: none, failed every anti-seizure med,        stopped at age 9.    -   Previous Meds: Anticonvulsants: Phenobarb, Valproic acid,        Lamictal, Topamax, Ceptra, Tegretol Antibiotics, Antifungals.

Clinical Profile:

i) General Chemistry test results prior to oral and intravenous PC

-   -   Electrolyte imbalance—low potassium −35%, low CO² ⁻³³%    -   Hepatic stress—decrease in cholesterol—34%    -   Poor nitrogen retention—low creatinine—135%

ii) Test results of red cell fatty acids

-   -   Elevation of very long chain fatty acid depicting        toxicity/suppressed peroxisomal function    -   Demyelination with suppress of 16.0 DMA −98%, 18.0 DMA −49%,        18.1 DMA −39%    -   Decreased Lipid content depicting poor membrane integrity—39%

Clinical Course:

Patient received oral and intravenous phospholipid therapy for 2 weeks.Patient exhibited a marked improvement in seizure activity, slowlydecreasing to 1 seizure nightly in the first week of phospholipidtherapy, and 1 seizure every other night in the second week. Aftercessation of the phospholipid therapy, there was an increase in seizureactivity.

The use of liquid cannabinoids mixed with BodyBio balancedphosphatidylcholine (PC) in a combination therapy results in a sharpdecrease in seizure activity approaching approximately 30% reduction inthe incidence of seizures compared to use of BodyBio balancedphosphatidylcholine (PC) therapy alone.

Example 4 Treatment of Patients with Alzheimer's Disease withCombination Therapy Case History: Alzheimer's Disease

Patient Background: A 74-year old male presents with a diagnosis ofAlzheimer's disease. Height: 5′10″, Weight: 140 lbs.

Presenting Symptoms include poor short term memory, cognitive deficits(unable to read a clock, difficulty following directions, poorfocus/attention, forgot the ability to use a computer, difficultyremembering where he placed objects, poor organization skills), anxiety,rage, word finding difficulty, aphasia, weight loss of 25# with reducedappetite, nocturia (up 2-3× each night), edema (ankles), pale skin,light sensitivity, blurred vision (no cataracts), vertigo at times,hoarseness, cold extremities (primarily hands, bilateral), muscleweakness in hands/arms, numbness in hands.

Dietary history: Self-imposed restriction of fat/oil and protein in thediet for the past 5 years for ‘health’ purposes

Family history of cancer, diabetes, cardiovascular disease CurrentMedications: none

Clinical Profile:

i) General chemistry test results prior to oral PC

-   -   Electrolyte imbalance—low potassium −45%, low sodium −35%, low        CO₂ −50%    -   Hepatic stress—decrease in cholesterol—75%    -   Hyperglycemia—increase in glucose+45%    -   Poor nitrogen retention—low creatinine—65%, low albumin—45%

ii) Test results of red cell fatty acids

-   -   Elevation of very long chain fatty acid depicting        toxicity/suppressed peroxisomal function    -   Overmyelination with increases of 16.0 DMA+311%, 18.0 DMA+125%,        18.1 DMA+226%    -   Decreased Lipid content depicting poor membrane integrity—87%    -   Deep suppression of Linoleic acid—73%    -   Suppression of Arachidonic acid—58%

Clinical Course:

Patient received oral phospholipid therapy for 4 months. His diet wasadjusted to increase protein and essential fatty acids were added asBodyBio Balance oil (linoleic acid) 2 Tablespoons twice daily andphosphatidylcholine liquid 1 Tablespoon twice daily. Patient experienced60% improvement in cognitive function including his attention, memory,organizational skills, and communication. His anxiety diminished, hisedema, pale skin tone, and numbness resolved. He gained muscle strengthand his episodes and duration of rage improved by 30%.

The use of liquid cannabinoids BodyBio balanced phosphatidylcholine (PC)combination therapy results in a sharp decrease in rage associatedbehavior including rage episodes and rage duration. The BodyBio balancedphosphatidylcholine (PC) combination therapy further addresses hisdeficits in attention, memory, organizational skills, and communicationand anxiety compared to use of BodyBio balanced phosphatidylcholine (PC)therapy alone.

Example 5 Treatment of Patients with Atherosclerosis with CombinationTherapy

Case History Cardio 101

Patient Background: A 59-year old male presents with atherosclerosis,hyperlipidemia, hypertension, and hyperthyroidism.

Symptoms include fatigue, back pain. Patient had a history of kidneystones.

Family history of atherosclerosis, cancer, hypertension, alcoholism,neurological disease

Current Medications: Thyroid, HCTZ/diuretic

Clinical Profile:

-   -   i) Test results before balanced PC cannabinoid combination        therapy:        -   Sharp increase in serum lipids with Triglycerides 581            (n=˜100)        -   Electrolyte imbalance—Potassium—33%        -   Elevation in very long chain fatty acids        -   Deficit in omega 6 gamma linolenic acid (GLA)—76% and            dihomogamma linolenic acid (DGLA)—48%        -   Deep suppression of red cell total lipid content—90%        -   Gross increase in dimethyl acetals (DMAs) reflective of an            increase in sphingomyelin.        -   16:0 DMA+128% 18:0 DMA+51% 18:1 DMA+20%        -   The dimethyl acetal status was determined by employing the            red blood cell fatty acid test at The Peroxisomal Diseases            Laboratory at the Kennedy Krieger Institute.    -   ii) Test results after high dose [two tablespoons at ˜45 grams        per Tbls (corresponding to a final concentration of Balanced        BodyBio PC of ˜52% [composed of a complex of phospholipids, and        of that complex ˜½ is phosphatidylcholine] or ˜12 grams of PC        per Tbls.] oral balanced PC cannabinoid combination therapy:    -   Stabilized Triglycerides 133 (n=˜100)    -   Electrolyte imbalance—Potassium −31%    -   Elevation in very long chain fatty acids    -   Continued deficit in omega 6 dihomogammal linolenic acid—60%    -   Red cell total lipid content normalized    -   Improvement in dimethyl acetal status reflective of        sphingomyelin membrane content    -   16:0 DMA+45% 18:0 DMA and 18:1 DMA Normalized (within +/−5% of        the zero baseline)

Clinical Course: The DMAs are higher in patients with atherosclerosisand/or atherosclerotic plaques which is due to a heightenedsphingomyelin to PC ratio. The use of the balanced PC alone to treatwith atherosclerosis and/or atherosclerotic plaques results in areduction of sphingomyelin (SM) at 45-50% of the membrane down to a˜20-25% concentration of SM value determined by measurement of thedimethyl acetyls (DMAs), with a corresponding return of the level of PCback towards its original normal 50% value. The use of Cannabis alone totreat the patient with atherosclerosis and/or atherosclerotic plaquesresults in no appreciable reduction of the sphingomyelin to PC ratio asdetermined by measurement of the dimethyl acetals (DMAs).

The patient with atherosclerosis and/or atherosclerotic plaques exhibitsa marked improvement in his disturbed lipid biochemistry following theuse of the balanced phosphatidylcholine cannabinoid combination therapywhich is greater than the effect achieved with treatment with thebalanced phosphatidylcholine alone. The patient also exhibits clinicalimprovement in cognition and energy which is greater than the effect ofimprovement in cognition and energy achieved with treatment with thebalanced phosphatidylcholine alone.

The improvement in the patient's conditions is attributed to the BodyBioInc balanced PC cannabinoid combination therapy which serves to reducethe sphingomyelin to PC ratio, and as a result, the DMAs are lowered bycompetitive inhibition.

The lowering of the DMA ratio results in a lowering of the plasminogensin the cell membrane which directly correlates with the loweredconcentration of sphingomylenin and calcium in the cell membrane. Thislowered concentration of sphingomyelin and calcium leads to anormalizing of the lipid bilayer membrane leaflets, a maximizing theintegrity of the membrane, a lowering of the incidence ofatherosclerosis and/or atherosclerotic plaques, and thus a more healthyheart, with the patient's sphingomyelin/PC ratios approaching a morenormalized ratio of approximately ˜20-25% to ˜45-50% level respectively.

Case History Cardio 102

Patient Background: A 60-year old male presents with atherosclerosis,hyperlipidemia, and multiple sclerosis (relapsing remitting)

Symptoms include fatigue, back pain, insomnia and muscle weakness

Family history of atherosclerosis, neurological disease

Current Medications: None

Clinical Profile:

-   -   i) Test results before balanced PC cannabinoid combination        therapy:    -   Increase in serum lipids with Triglycerides 155 (n=˜100)    -   Electrolyte imbalance—Sodium+30%, CO2—25%, Calcium +43%    -   Elevation in very long chain fatty acids    -   Deficit in omega 6 gamma arachidonic acid—103%    -   Deep suppression of red cell total lipid content—70%    -   Gross increase in dimethyl acetals reflective of an increase in        sphingomyelin    -   16:0 DMA+180% 18:0 DMA+134% 18:1 DMA+166%

The dimethyl acetal status was determined by employing the red bloodcell fatty acid test as described supra.

-   -   ii) Test results after high dose oral balanced PC cannabinoid        combination therapy as described supra:    -   Stabilized Triglycerides 116 (n=˜100)    -   Electrolyte imbalance—Sodium+30%, CO₂ —25%, Calcium+43%    -   Elevation in very long chain fatty acids    -   Deficit in omega 6 arachidonic acid improved—59%    -   Red cell total lipid content normalized    -   Improvement in dimethyl acetal status reflective of        sphingomyelin membrane content    -   16:0 DMA, 18:0 DMA and 18:1 DMA all corrected (within +/−5% of        the zero baseline).

Clinical Course: The DMAs are higher in atherosclerosis which is due toa heightened sphingomyelin to PC ratio. The patient has markedimprovement in his disturbed lipid biochemistry following the use of thebalanced phosphatidylcholine cannabinoid combination therapy. Thepatient also exhibits clinical improvement involved muscular and cardiacimprovement. The improvement in his conditions is attributed to theBodyBio Inc balanced PC cannabinoid combination therapy which serves toreduce the sphingomyelin to PC ratio, and as a result, the DMAs arelowered.

The lowering of the DMA ratio results in a lowering of the plasminogensin the cell membrane which directly correlates with the loweredconcentration of sphingomylenin and calcium in the cell membrane. Thislowered concentration of sphingomylenin and calcium leads to anormalizing of the lipid bilayer membrane leaflets, a maximizing theintegrity of the membrane, a lowering of the incidence ofatherosclerosis and/or atherosclerotic plaques, and thus a more healthyheart, with the patient's sphingomyelin/PC ratios approaching a morenormalized ratio of approximately 20%/50%, respectively.

Case History Cardio 103

Patient Background: A 76-year old male presents with an atherosclerosis,hyperlipidemia, bronchiectasis, atrial fibrillation, hypercoagulation,and post stroke.

Symptoms include fatigue, muscle weakness, shortness of breath, frequenturination, and sinusitis.

Family history of atherosclerosis and stroke.

Current Medications: Warfarin, antibiotics

Clinical Profile:

-   -   i) Test results before balanced PC cannabinoid combination        therapy:    -   Sharp increase in serum lipids with LDL 181 (n=˜100);        Cholesterol 270    -   Electrolyte imbalance—increase in sodium +40    -   Sharp elevation in very long chain fatty acids, odd chain fatty        acids    -   Gross deficit in omega 6 gamma linolenic acid −81%; dihomogamma        linolenic acid −106%    -   Depression in red cell total lipid content −89%    -   Gross increase in dimethyl acetals reflective of an increase in        sphingomyelin    -   16:0 DMA+136% 18:0 DMA+94% 18:1 DMA+101%

The dimethyl acetal status was determined by employing the red bloodcell fatty acid test as described supra.

-   -   ii) Test results after high dose oral balanced PC cannabinoid        combination therapy as described supra:    -   Slightly improved LDL 154 (n=˜100); Cholesterol 243    -   Electrolyte imbalance—increase in sodium +50    -   Sharp elevation in very long chain fatty acids, odd chain fatty        acids

Continued deficit in omega 6 gamma linolenic acid −81% and dihomogammalinolenic acid −102% due to poor compliance in taking oral lipidsupplements

Red cell total lipid content normalized

Improvement in dimethyl acetal status reflective of sphingomyelinmembrane content

16:0 DMA+67% 18:0 DMA +47% 18:1 DMA 53%

Clinical Course: The DMAs are higher in atherosclerosis which is due toa heightened sphingomyelin to PC ratio. Patient was resistant to takinghis oral lipids but did receive intravenous phospholipid cannabinoidcombination therapy. The Patient has marked improvement in theDMA/sphingomyelin status, stabilization of membrane phospholipids(normalization of red cell content) and serum lipids (triglyceridesdecreased) following the use of the balanced phosphatidylcholinecannabinoid combination therapy.

The Patient also exhibits clinical improvement in regard to fatigue,muscle strength, lung capacity and alertness. The improvement in hisconditions is attributed to the BodyBio Inc balanced PC cannabinoidcombination therapy which serves to reduce the sphingomyelin to PCratio, and as a result, the DMAs are lowered.

The lowering of the DMA ratio results in a lowering of the plasminogensin the cell membrane which directly correlates with the loweredconcentration of sphingomylenin and calcium in the cell membrane. Thislowered concentration of sphingomyelin and calcium leads to anormalizing of the lipid bilayer membrane leaflets, a maximizing theintegrity of the membrane, a lowering of the incidence ofatherosclerosis and/or atherosclerotic plaques, and thus a more healthyheart, with the patient's sphingomyelin/PC ratios approaching a morenormalized ratio of approximately 20%/50%, respectively.

Without intended to be limited to any particular mechanism of action, itis believed that the combination of BodyBio's balancedPhosphatidylcholine with one or more cannabinoids in the context ofpatients with atherosclerosis and/or atherosclerotic plaques may have i)interactions with one or more elements of the cell membrane; ii) directactions on isolated arteries, causing both acute and time-dependentvasorelaxation, iii) protection against the vascular damage caused by ahigh glucose environment; and/or reduction of the vascularhyperpermeability associated with such cell membrane environments.

For example, and not by way of limitation, it has been shown by othersthat CB1 receptors are expressed in the human coronary atheromata,particularly in lesional macrophages, and that and that theendocannabinoid system was activated in patients with CAD. It has alsobeen shown that CB1 receptor blockade significantly reduced theproduction of the proinflammatory mediators from human macrophages(Sugamura K, Sugiyama S, Nozaki T, et. al. 2009 Jan. 6; 119(1):28-36).These results indicate the presence and activation of theendocannabinoid system in human atherosclerosis and suggest that CB1receptor blockade modulates the inflammatory state in atheromata throughits anti-inflammatory effects on macrophages.

The inclusion of one or more cannabinoids in combination with BodyBio'sbalanced Phosphatidylcholine may serve to function similarly to theendocannabinoids and synergystically bring about the blockade of one ormore moieties in the cell membrane, including, for example, the CB1receptor. The blockade of the CB1 receptor in turn modulates theinflammatory state in atheromata, which in turn in combination withBodyBio's balanced Phosphatidylcholine serves to reduce thesphingomyelin to PC ratio, and as a result, the DMAs are lowered bycompetitive inhibition.

The lowering of the DMA ratio results in a lowering of the plasminogensin the cell membrane which directly correlates with the loweredconcentration of sphingomylenin and calcium in the cell membrane. Thislowered concentration of sphingomylenin and calcium leads to anormalizing of the lipid bilayer membrane leaflets, a maximizing theintegrity of the membrane, a lowering of the incidence ofatherosclerosis and/or atherosclerotic plaques, and thus a more healthyheart, with the patient's sphingomyelin/PC ratios approaching morenormalized ratios.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a,” “an” and “the” and similar references in thecontext of this disclosure (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,such as, preferred, preferably) provided herein, is intended merely tofurther illustrate the content of the disclosure and does not pose alimitation on the scope of the claims. No language in the specificationshould be construed as indicating any non-claimed element as essentialto the practice of the present disclosure.

The use of individual numerical values are stated as approximations asthough the values were preceded by the word “about” or “approximately.”Similarly, the numerical values in the various ranges specified in thisapplication, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about” or “approximately.”In this manner, variations above and below the stated ranges can be usedto achieve substantially the same results as values within the ranges.As used herein, the terms “about” and “approximately” when referring toa numerical value shall have their plain and ordinary meanings to aperson of ordinary skill in the art to which the disclosed subjectmatter is most closely related or the art relevant to the range orelement at issue. The amount of broadening from the strict numericalboundary depends upon many factors. For example, some of the factorswhich may be considered include the criticality of the element and/orthe effect a given amount of variation will have on the performance ofthe claimed subject matter, as well as other considerations known tothose of skill in the art. As used herein, the use of differing amountsof significant digits for different numerical values is not meant tolimit how the use of the words “about” or “approximately” will serve tobroaden a particular numerical value or range. Thus, as a generalmatter, “about” or “approximately” broaden the numerical value. Also,the disclosure of ranges is intended as a continuous range includingevery value between the minimum and maximum values plus the broadeningof the range afforded by the use of the term “about” or “approximately.”Thus, recitation of ranges of values herein are merely intended to serveas a shorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein.

It is to be understood that any ranges, ratios and ranges of ratios thatcan be formed by, or derived from, any of the data disclosed hereinrepresent further embodiments of the present disclosure and are includedas part of the disclosure as though they were explicitly set forth. Thisincludes ranges that can be formed that do or do not include a finiteupper and/or lower boundary. Accordingly, a person of ordinary skill inthe art most closely related to a particular range, ratio or range ofratios will appreciate that such values are unambiguously derivable fromthe data presented herein.

Alternative embodiments of the claimed disclosure are described herein,including the best mode known to the inventors for practicing theclaimed invention. Of these, variations of the disclosed embodimentswill become apparent to those of ordinary skill in the art upon readingthe foregoing disclosure. The inventors expect skilled artisans toemploy such variations as appropriate (e.g., altering or combiningfeatures or embodiments), and the inventors intend for the invention tobe practiced otherwise than as specifically described herein.

Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

1. A method for treating a subject suffering from anxiety disordercomprising: (a) a therapeutically effective amount of a firstcomposition comprising a balanced phosphatidylcholine (PC); and (b) atherapeutically effective amount of a second composition comprising oneor more cannabinoids, the balanced PC composition is a water-solublesupplement extracted from soy lecithin that comprises phospholipids andessential fatty acids; the phospholipids comprise phosphatidylcholine,phosphatidylethanolamine, and phosphatidylinositol; and the essentialfatty acids comprise omega 6 and omega 3 fatty acids in a ratio of 4:1respectively, and a pharmaceutically acceptable carrier or diluent,wherein symptoms of anxiety are ameliorated or treated.
 2. The methodaccording to claim 1, wherein said anxiety comprises generalized anxietydisorder, panic disorder, phobias, obsessive-compulsive disorder,post-traumatic stress disorder, and separation anxiety disorder.
 3. Themethod according to claim 1, wherein the one or more cannabinoidscomprise natural or synthetic variants of cannabinoids.
 4. The methodaccording to claim 3, wherein the natural cannabinoids comprise thoseCannabis-Derived Cannabinoids comprising Cannabinoids obtained fromCannabis indica plant comprising Cannabidiol (CBD), Cannabinol (CBN),Cannabigerol (CBG); Cannabichromene (CBC); Cannabicyclol (CBL);Cannabivarin (CBV); Tetrahydrocannabivarin (THCV); Cannabidivarin(CBDV); Cannabichromevarin (CBCV); Cannabigerovarin (CBGV); CannabigerolMonomethyl Ether (CBGM); and Tetrahydrocannabinol (THC), or acombination thereof.
 5. The method of claim 4, wherein the naturalcannabinoids further comprise phytocannabinoids derived from Echinaceapurpurea, Echinacea angustifolia, Echinacea pallida, Acmella oleracea,Helichrysum umbraculigerum, and Radula marginata, or a combinationthereof.
 6. The method of claim 3, wherein the synthetic cannabinoidvariants comprise Dronabinol (Marinol) (Δ9-tetrahydrocannabinol (THC)),Nabilone (Cesamet), Sativex, and Rimonabant (SR141716), or a combinationthereof.
 7. The method according to claim 1, wherein the balanced PCcomposition and the cannabinoids, are formulated in one or differentsolutions.
 8. The method according to claim 1, wherein the balanced PCcomposition and the cannabinoids are in a dry or a liquid formulation.9. The method according to claim 1, wherein the balanced PC compositionand the cannabinoids are administered contemporaneously or at differenttime intervals.
 10. A method for treating, or ameliorating one or moresymptoms of seizure, alzheimer's, atherosclerosis, anxiety or depressionin a subject comprising administering to said subject (a) atherapeutically effective amount of a first composition comprising abalanced PC composition; and (b) a therapeutically effective amount of asecond composition comprising one or more cannabinoids, the balanced PCcomposition is a water-soluble supplement extracted from soy lecithinthat comprises phospholipids and essential fatty acids; thephospholipids comprise phosphatidylcholine, phosphatidylethanolamine,and phosphatidylinositol; and the essential fatty acids comprise omega 6and omega 3 fatty acids in a ratio of 4:1 respectively, wherein saidfirst composition and said second composition are administeredcontemporaneously, together with a pharmaceutically acceptable carrieror diluent.
 11. The method of claim 10, wherein the balanced PCcomposition and the cannabinoids are administered at different timeintervals.
 12. The method of claim 10, wherein the balanced PCcomposition, the cannabinoids, or both are administered parenterally,transdermally, intranasally, orally or intravenously.
 13. The method ofclaim 10, wherein the balanced PC composition and the cannabinoids areadministered successively, contemporaneously, or both, at different timeintervals.
 14. The method of claim 10, wherein the balanced PCcomposition and the cannabinoids are administered or in a time-releasedmanner.
 15. The method of claim 10, wherein the balanced PC compositionand the cannabinoids are formulated in one or more solutionformulations.
 16. A kit for treating or ameliorating one or moresymptoms of seizures alzheimer's, atherosclerosis, anxiety or depressioncomprising: a) a first composition comprising a BodyBio balanced PCcomposition; b) a second composition comprising one or morecannabinoids; and c) instructions for the use of the first and secondcompositions and the constituents.
 17. A method of achieving an enhancedtherapeutic effectiveness of cannabinoids in a subject suffering fromsymptoms of seizure, alzheimer's, atherosclerosis, anxiety or depressioncomprising administrating one or more cannabinoids in combination with abalanced phosphatidylcholine composition, wherein the effectivetherapeutic concentration of the one or more cannabinoids is reduced byabout 10-100 fold when administered with said balancedphosphatidylcholine as compared to a control group that had beenadministered said cannabinoids alone.
 18. The method of claim 17,wherein reduced dosing of cannabinoids results in prevention oramelioration of one or more side effects or symptoms of use ofcannabinoids comprising dysphoria, anxiety, panic, impairment of memory,reductions in psychomotor and cognitive performance, disorderedperception of the passage of time, euphoria, schizophrenic psychosis,tiredness, dizziness, tachycardia, orthostatic hypotension, dry mouth,reduced lacrimation, muscle relaxation, increased appetite, potentialirreversible cognitive impairments, or any combination thereof.